Process for making substituted pyrazoles

ABSTRACT

This invention is directed generally to a process for making substituted pyrazoles, tautomers of the substituted pyrazoles, and salts of the substituted pyrazoles and tautomers. The substituted pyrazoles correspond in structure to Formula (I): 
                 
 
wherein R 3A , R 3B , R 3C , Y 1 , Y 2 , Y 3 , Y 4 , and Y 5  are as defined in the specification.

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

This patent claims priority to U.S. Provisional Application Ser. No.60/383,691 (filed May 28, 2002); Ser. No. 60/381,261 (filed May 17,2002); and Ser. No. 60/324,987 (filed Sep. 25, 2001). The entire text ofeach of those applications is incorporated by reference into thisapplication.

FIELD OF THE INVENTION

This invention is directed to a process for making substitutedpyrazoles, including tautomers of the substituted pyrazoles, and saltsof the substituted pyrazoles and tautomers. This invention also isdirected to compositions (including methods for making suchcompositions) comprising compounds that may be used as intermediates insuch a process. This invention is additionally directed topharmaceutical compositions (including methods for making suchcompositions) comprising substituted pyrazoles, tautomers, andpharmaceutically-acceptable salts prepared by such a process. Thisinvention is further directed to using compounds, tautomers, andpharmaceutically-acceptable salts prepared by such a process to treatvarious conditions.

BACKGROUND OF THE INVENTION

Mitogen-activated protein kinases (MAP) is a family of proline-directedserine/threonine kinases that activate their substrates by dualphosphorylation. The kinases are activated by a variety of signals,including nutritional and osmotic stress, UV light, growth factors,endotoxin, and inflammatory cytokines. The p38 MAP kinase group is a MAPfamily of various isoforms, including p38α, p38β, and p38γ. Thesekinases are responsible for phosphorylating and activating transcriptionfactors (e.g., ATF2, CHOP, and MEF2C), as well as other kinases (e.g.,MAPKAP-2 and MAPKAP-3). The p38 isoforms are activated by bacteriallipopolysaccharide, physical and chemical stress, and pro-inflammatorycytokines, including tumor necrosis factor (“TNF”) and interleukin-1(“IL-1”). The products of the p38 phosphorylation mediate the productionof inflammatory cytokines, including TNF, IL-1, and cyclooxygenase-2.

It is believed that p38α kinase can cause or contribute to the effectsof, for example, inflammation generally; arthritis; neuroinflammation;pain; fever; pulmonary disorders; cardiovascular diseases;cardiomyopathy; stroke; ischemia; reperfusion injury; renal reperfusioninjury; brain edema; neurotrauma and brain trauma; neurodegenerativedisorders; central nervous system disorders; liver disease andnephritis; gastrointestinal conditions; ulcerative diseases; ophthalmicdiseases; ophthalmological conditions; glaucoma; acute injury to the eyetissue and ocular traumas; diabetes; diabetic nephropathy; skin-relatedconditions; viral and bacterial infections; myalgias due to infection;influenza; endotoxic shock; toxic shock syndrome; autoimmune disease;bone resorption diseases; multiple sclerosis; disorders of the femalereproductive system; pathological (but non-malignant) conditions, suchas hemaginomas, angiofibroma of the nasopharynx, and avascular necrosisof bone; benign and malignant tumors/neoplasia including cancer;leukemia; lymphoma; systemic lupus erthrematosis (SLE); angiogenesisincluding neoplasia; and metastasis.

TNF is a cytokine produced primarily by activated monocytes andmacrophages. Excessive or unregulated TNF production (particularlyTNF-α) has been implicated in mediating a number of diseases. It isbelieved, for example, that TNF can cause or contribute to the effectsof inflammation (e.g., rheumatoid arthritis and inflammatory boweldisease), asthma, autoimmune disease, graft rejection, multiplesclerosis, fibrotic diseases, cancer, fever, psoriasis, cardiovasculardiseases (e.g., post-ischemic reperfusion injury and congestive heartfailure), pulmonary diseases (e.g., hyperoxic alveolar injury),hemorrhage, coagulation, radiation damage, and acute phase responseslike those seen with infections and sepsis and during shock (e.g.,septic shock and hemodynamic shock). Chronic release of active TNF cancause cachexia and anorexia. And TNF can be lethal.

TNF also has been implicated in infectious diseases. These include, forexample, malaria, mycobacterial infection, meningitis. These alsoinclude viral infections, such as HIV, influenza virus, and herpesvirus, including herpes simplex virus type-1 (HSV-1), herpes simplexvirus type-2 (HSV-2), cytomegalovirus (CMV), varicella-zoster virus(VZV), Epstein-Barr virus, human herpesvirus-6 (HHV-6), humanherpesvirus-7 (HHV-7), human herpesvirus-8 (HHV-8), pseudorabies andrhinotracheitis, among others.

IL-8 is another pro-inflammatory cytokine, which is produced bymononuclear cells, fibroblasts, endothelial cells, and keratinocytes.This cytokine is associated with conditions including inflammation.

IL-1 is produced by activated monocytes and macrophages, and is involvedin inflammatory responses. IL-1 plays a role in many pathophysiologicalresponses, including rheumatoid arthritis, fever, and reduction of boneresorption.

TNF, IL-1, and IL-8 affect a wide variety of cells and tissues, and areimportant inflammatory mediators of a wide variety of conditions. Theinhibition of these cytokines by inhibition of the p38 kinase isbeneficial in controlling, reducing, and alleviating many of thesedisease states.

Various pyrazoles have previously been described:

In U.S. Pat. No. 4,000,281, Beiler and Binon report 4,5-aryl/heteroarylsubstituted pyrazoles with antiviral activity against both RNA and DNAviruses, such as myxoviruses, adenoviruses, rhinoviruses, and variousviruses of the herpes group.

WIPO Int'l Publ. No. WO 92/19615 (published Nov. 12, 1992) describespyrazoles as novel fungicides.

In U.S. Pat. No. 3,984,431, Cueremy and Renault report derivatives ofpyrazole-5-acetic acid as having anti-inflammatory activity, with[1-isobutyl-3,4-diphenyl-1H-pyrazol-5-yl]acetic acid being specificallydescribed.

In U.S. Pat. No. 3,254,093, Hinsgen et al. report a process forpreparing pyrazoles.

WIPO Int'l Publ. No. WO 83/00330 (published Feb. 3, 1983) describes aprocess for preparing diphenyl-3,4-methyl-5-pyrazole derivatives.

WIPO Int'l Publ. No. WO 95/06036 (published Mar. 2, 1995 reports aprocess for preparing pyrazole derivatives.

In U.S. Pat. No. 5,589,439, T. Goto, et al. report tetrazole derivativesand their use as herbicides.

EP 515,041 reports pyrimidinyl substituted pyrazole derivatives as novelagricultural fungicides.

Japanese Patent 4,145,081 reports pyrazolecarboxylic acid derivatives asherbicides.

Japanese Patent 5,345,772 reports novel pyrazole derivatives asinhibiting acetylcholinesterase.

Pyrazoles have been reported as useful in treating inflammation.

Japanese Patent 5,017,470 reports synthesis of pyrazole derivatives asanti-inflammatory, anti-rheumatic, anti-bacterial, and anti-viral drugs.

EP 115640 (published Dec. 30, 1983) reports 4-imidazolyl-pyrazolederivatives as inhibitors of thromboxane synthesis, with3-(4-Isopropyl-1-methylcyclohex-1-yl)-4-(imidazol-1-yl)-1H-pyrazolebeing specifically described.

WIPO Int'l Publ. No. WO 97/01551 (published Jan. 16, 1997) reportssubstituted pyrazoles as adenosine antagonists, with4-(3-Oxo-2,3-dihydropyridazin-6-yl)-3-phenylpyrazole being specificallydescribed.

In U.S. Pat. No. 5,134,142, to Matsuo et al. report 1,5-diaryl pyrazolesas having anti-inflammatory activity.

In U.S. Pat. No. 5,559,137, Adams et al. report pyrazoles(1,3,4,-substituted) as inhibitors of cytokines used in the treatment ofcytokine diseases, with3-(4-fluorophenyl)-1-(4-methylsulfinylphenyl)-4-(4-pyridyl)-5H-pyrazolebeing specifically described.

WIPO Int'l Publ. No. WO 96/03385 (published Feb. 8, 1996) reports3,4-substituted pyrazoles as having anti-inflammatory activity, with3-methylsulfonylphenyl-4-aryl-pyrazoles and3-aminosulfonylphenyl-4-aryl-pyrazoles being specifically described.

Laszlo et al., Bioorg. Med. Chem. Letters, 8 (1998) 2689-2694, describescertain furans, pyrroles, and pyrazolones, particularly3-pyridyl-2,5-diaryl-pyrroles, as inhibitors of p38 kinase.

WIPO Int'l Publ. No. WO 98/52940 (PCT Patent Application No. US98/10436published on Nov. 26, 1998) reports pyrazoles, compositions containingthose pyrazoles, and methods for treating p38-mediated disorders usingthose pyrazoles.

WIPO Int'l Publ. No. WO 00/31063 (PCT Patent Application No. US99/26007published on Jun. 2, 2000) also reports pyrazoles, compositionscontaining those pyrazoles, and methods for making pyrazoles.

In view of the importance of pyrazoles in the prevention and treatmentof several pathological conditions (particularly those associated withp38 kinase activity, TNF activity, and/or cyclooxygenase-2 activity),there continues to be a need for processes for making substitutedpyrazoles. The following disclosure describes such a process.

SUMMARY OF THE INVENTION

This invention is directed to a method for making substituted pyrazolesthat tend to inhibit p38 kinase activity, TNF activity, and/orcyclooxygenase-2 activity.

Briefly, therefore, this invention is directed, in part, to a processfor making a substituted pyrazole, a tautomer of the substitutedpyrazole, or a salt of the substituted pyrazole or tautomer. Thesubstituted pyrazole corresponds in structure to Formula (I):

Here:

-   -   R^(3A), R^(3B), and R^(3C) are independently selected from the        group consisting of hydrogen, halogen, hydroxy, cyano, amino,        alkyl, aminoalkyl, monoalkylamino, dialkylamino, alkoxy, and        alkoxyalkyl. Any carbon of the alkyl, aminoalkyl,        monoalkylamino, dialkylamino, alkoxy, or alkoxyalkyl optionally        is substituted with one or more substituents independently        selected from the group consisting of halogen, hydroxy, and        cyano.

One of Y¹, Y², Y³, Y⁴, and Y⁵ is ═C(R⁴)—. One of Y¹, Y², Y³, Y⁴, and Y⁵is ═N—. And three of Y¹, Y², Y³, Y⁴, and Y⁵ are independently selectedfrom the group consisting of ═C(H)— and ═N—.

R⁴ is hydrogen, halogen, cyano, hydroxy, thiol, carboxy, nitro, alkyl,carboxyalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylcarbonyl,carbocyclyl, carbocyclylalkyl, carbocyclylalkenyl, carbocyclyloxy,carbocyclylalkoxy, carbocyclyloxyalkyl, carbocyclylthio,carbocyclylsulfinyl, carbocyclylsulfonyl, heterocyclylthio,heterocyclylsulfinyl, heterocyclylsulfonyl, carbocyclylalkoxy,carbocyclylheterocyclyl, heterocyclylalkyl, heterocyclyloxy,heterocyclylalkoxy, amino, aminoalkyl, alkylamino, alkenylamino,alkynylamino, carbocyclylamino, heterocyclylamino, aminocarbonyl,alkoxy, alkoxyalkyl, alkenyloxyalkyl, alkoxyalkylamino,alkylaminoalkoxy, alkoxycarbonyl, carbocyclyloxycarbonyl,heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxycarbocyclylamino,alkoxycarbocyclylalkylamino, aminosulfinyl, aminosulfonyl,alkylsulfonylamino, alkoxyalkoxy, aminoalkoxy, aminoalkylamino,alkylaminoalkylamino, carbocyclylalkylamino,alkylaminoalkylaminoalkylamino, alkylheterocyclylamino,heterocyclylalkylamino, alkylheterocyclylalkylamino,carbocyclylalkylheterocyclylamino, heterocyclylheterocyclylalkylamino,alkoxycarbonylheterocyclylamino, alkylaminocarbonyl, alkylcarbonylamino,hydrazinyl, alkylhydrazinyl, or carbocyclylhydrazinyl. Any substitutablemember of such group optionally is substituted with one or moresubstituents independently selected from the group consisting of alkyl,alkenyl, hydroxy, halogen, haloalkyl, alkoxy, haloalkoxy, keto, amino,nitro, cyano, alkylsulfonyl, alkylsulfinyl, alkylthio, alkoxyalkyl,carbocyclyloxy, heterocyclyl, and heterocyclylalkoxy.

In one embodiment, the process comprises forming a mixture by a processcomprising introducing a hydrazone and an optionally-substituted benzoylhalide into a reactor. This mixture is the heated to a temperature ofgreater than 50° C. Here, the hydrazone corresponds in structure toFormula (II):

The optionally-substituted benzoyl halide corresponds in structure toFormula (III):

And R^(B) is halogen.

In another embodiment, the process comprises forming a composition.Greater than 30% (by weight) of this composition consists of a protectedpyrazole intermediate corresponding in structure to Formula (IV):

In another embodiment, the process comprises contacting an acid andtoluene with a protected pyrazole intermediate corresponding instructure to Formula (IV).

In another embodiment, the process comprises contacting a protectedpyrazole intermediate corresponding in structure to Formula (IV) with anacid to form an acidic mixture. This acidic mixture is subsequentlycontacted with a base. The temperature of the acidic mixture ismaintained at less than 65° C. between the time the acidic mixture isformed and the time a base is added to the acidic mixture.

In another embodiment, the process comprises contacting a protectedpyrazole intermediate corresponding in structure to Formula (IV) with anacid to form an acidic mixture. The acidic mixture is subsequentlycontacted with a base to form a mixture having a greater pH. Thismixture with a greater pH is subsequently heated to a temperature ofgreater than 25° C.

In another embodiment, the process comprises contacting an unsubstitutedpiperidinyl intermediate with acetonitrile. Here, the unsubstitutedpiperidinyl intermediate corresponds in structure to Formula (V):

In another embodiment, the process comprises reacting a glycolic acidester with an unsubstituted piperidinyl intermediate corresponding instructure to Formula (V).

This invention also is directed, in part, to compositions (and methodsof making such compositions) comprising compounds that may be used asintermediates of the above-described process. Greater than 30% (byweight) of these compositions consists of a compound corresponding instructure to Formula (IV).

This invention is also directed, in part, to pharmaceutical compositions(or medicaments) comprising the compounds, tautomers, and salts made inaccordance with this invention.

This invention is also directed, in part, to methods of makingpharmaceutical compositions comprising the compounds, tautomers, andsalts made in accordance with this invention.

This invention is also directed, in part, to methods of treatment usingthe compounds, tautomers, and salts made in accordance with thisinvention.

Further benefits of Applicants' invention will be apparent to oneskilled in the art from reading this specification.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

This detailed description of preferred embodiments is intended only toacquaint others skilled in the art with Applicants' invention, itsprinciples, and its practical application so that others skilled in theart may adapt and apply the invention in its numerous forms, as they maybe best suited to the requirements of a particular use. This detaileddescription and its specific examples, while indicating preferredembodiments of this invention, are intended for purposes of illustrationonly. This invention, therefore, is not limited to the preferredembodiments described in this specification, and may be variouslymodified.

A. Compounds that may be Prepared by the Methods of this Invention

The compounds that may be prepared by the method of this inventioninclude compounds corresponding in structure to the following Formula(I):

Here:

R^(3A), R^(3B), and R^(3C) are independently selected from the groupconsisting of hydrogen, halogen, hydroxy, cyano, amino, alkyl,aminoalkyl, monoalkylamino, dialkylamino, alkoxy, and alkoxyalkyl. Anycarbon of the alkyl, aminoalkyl, monoalkylamino, dialkylamino, alkoxy,or alkoxyalkyl optionally is substituted with one or more substituentsindependently selected from the group consisting of halogen, hydroxy,and cyano.

In some preferred embodiments, R^(3C) is hydrogen; and R^(3A) and R^(3B)are independently selected from the group consisting of halogen,hydroxy, cyano, amino, alkyl, aminoalkyl, monoalkylamino, dialkylamino,alkoxy, and alkoxyalkyl. Any carbon of the alkyl, amino alkyl, monoalkyl amino, dialkylamino, alkoxy, or alkoxyalkyl optionally issubstituted with one or more substituents independently selected fromthe group consisting of halogen, hydroxy, and cyano. In some suchembodiments, the compound corresponds in structure to Formula (I-A):

In other embodiments, the compound corresponds in structure to Formula(I-B):

In other embodiments, the compound corresponds in structure to Formula(I-C):

In other embodiments, the compound corresponds in structure to Formula(I-D):

In other embodiments, the compound corresponds in structure to Formula(I-E):

In other embodiments, the compound corresponds in structure to Formula(I-F):

In some preferred embodiments, R^(3B) and R^(3C) are each hydrogen; andR^(3A) is halogen, hydroxy, cyano, amino, alkyl, aminoalkyl,monoalkylamino, dialkylamino, alkoxy, or alkoxyalkyl. Any carbon of thealkyl, aminoalkyl, monoalkylamino, dialkylamino, alkoxy, or alkoxyalkyloptionally is substituted with one or more substituents independentlyselected from the group consisting of halogen, hydroxy, and cyano. Insome such embodiments, the compound corresponds in structure to Formula(I-G):

In some other embodiments, the compound corresponds in structure toFormula (I-H):

In some other embodiments, the compound corresponds in structure toFormula (I-I):

In some preferred embodiments, R^(3A), R^(3B), and R^(3C) areindependently selected from the group consisting of hydrogen, chloro,fluoro, hydroxy, cyano, amino, methyl, trifluoromethyl, ethyl, methoxy,and trifluoromethoxy.

In some preferred embodiments, R^(3C) is hydrogen; and R^(3A) and R^(3B)are independently selected from the group consisting of chloro, fluoro,hydroxy, cyano, amino, methyl, trifluoromethyl, ethyl, methoxy, andtrifluoromethoxy.

In some preferred embodiments, R^(3B) and R^(3C) are each hydrogen; andR^(3A) is chloro, fluoro, hydroxy, cyano, amino, methyl,trifluoromethyl, ethyl, methoxy, or trifluoromethoxy.

One of Y¹, Y², Y³, Y⁴, and Y⁵ is ═C(R⁴)—, i.e., a carbon atom doublebonded to one atom, single bonded to an R⁴ substituent, and singlebonded to yet another atom:

One of Y¹, Y², Y³, Y⁴, and Y⁵ is ═N—, i.e., a nitrogen atom doublebonded to one atom and single bonded to another atom:

And three of Y¹, Y², Y³, Y⁴, and Y⁵ are independently selected from thegroup consisting of ═C(H)— and ═N—, i.e., three of Y¹, Y², Y³, Y⁴, andY⁵ are independently selected from the group consisting of ═:

In some preferred embodiments, Y¹ is ═C(H)— or ═N—; Y² is ═C(R⁴)—; Y³ is═N—; and Y⁴ and Y⁵ are each ═C(H)—.

In some preferred embodiments, Y¹ and Y³ are each ═N—, Y² is ═C(R⁴)—,and Y⁴ and Y⁵ are each ═C(H)—.

In some preferred embodiments, Y¹ and Y³ are each ═N—; and Y², Y⁴, andY⁵ are each ═C(H)—.

In some preferred embodiments, Y¹, Y², Y⁴, and Y⁵ are each ═C(H)—; andY³ is ═N—.

R⁴ is hydrogen, halogen, cyano, hydroxy, thiol, carboxy, nitro, alkyl,carboxyalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylcarbonyl,carbocyclyl, carbocyclylalkyl, carbocyclylalkenyl, carbocyclyloxy,carbocyclylalkoxy, carbocyclyloxyalkyl, carbocyclylthio,carbocyclylsulfinyl, carbocyclylsulfonyl, heterocyclylthio,heterocyclylsulfinyl, heterocyclylsulfonyl, carbocyclylalkoxy,carbocyclylheterocyclyl, heterocyclylalkyl, heterocyclyloxy,heterocyclylalkoxy, amino, aminoalkyl, alkylamino, alkenylamino,alkynylamino, carbocyclylamino, heterocyclylamino, aminocarbonyl,alkoxy, alkoxyalkyl, alkenyloxyalkyl, alkoxyalkylamino,alkylaminoalkoxy, alkoxycarbonyl, carbocyclyloxycarbonyl,heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxycarbocyclylamino,alkoxycarbocyclylalkylamino, aminosulfinyl, aminosulfonyl,alkylsulfonylamino, alkoxyalkoxy, aminoalkoxy, aminoalkylamino,alkylaminoalkylamino, carbocyclylalkylamino,alkylaminoalkylaminoalkylamino, alkylheterocyclylamino,heterocyclylalkylamino, alkylheterocyclylalkylamino,carbocyclylalkylheterocyclylamino, heterocyclylheterocyclylalkylamino,alkoxycarbonylheterocyclylamino, alkylaminocarbonyl, alkylcarbonylamino,hydrazinyl, alkylhydrazinyl, or carbocyclylhydrazinyl. Any substitutablemember of such group optionally is substituted with one or moresubstituents independently selected from the group consisting of alkyl,alkenyl, hydroxy, halogen, haloalkyl, alkoxy, haloalkoxy, keto, amino,nitro, cyano, alkylsulfonyl, alkylsulfinyl, alkylthio, alkoxyalkyl,carbocyclyloxy, heterocyclyl, and heterocyclylalkoxy.

In some preferred embodiments, R⁴ is halogen, cyano, hydroxy, thiol,carboxy, nitro, alkyl, carboxyalkyl, alkylthio, alkylsulfinyl,alkylsulfonyl, alkylcarbonyl, carbocyclyl, carbocyclylalkyl,carbocyclylalkenyl, carbocyclyloxy, carbocyclylalkoxy,carbocyclyloxyalkyl, carbocyclylthio, carbocyclylsulfinyl,carbocyclylsulfonyl, heterocyclylthio, heterocyclylsulfinyl,heterocyclylsulfonyl, carbocyclylalkoxy, carbocyclylheterocyclyl,heterocyclylalkyl, heterocyclyloxy, heterocyclylalkoxy, amino,aminoalkyl, alkylamino, alkenylamino, alkynylamino, carbocyclylamino,heterocyclylamino, aminocarbonyl, alkoxy, alkoxyalkyl, alkenyloxyalkyl,alkoxyalkylamino, alkylaminoalkoxy, alkoxycarbonyl,carbocyclyloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino,alkoxycarbocyclylamino, alkoxycarbocyclylalkylamino, aminosulfinyl,aminosulfonyl, alkylsulfonylamino, alkoxyalkoxy, aminoalkoxy,aminoalkylamino, alkylaminoalkylamino, carbocyclylalkylamino,alkylaminoalkylaminoalkylamino, alkylheterocyclylamino,heterocyclylalkylamino, alkylheterocyclylalkylamino,carbocyclylalkylheterocyclylamino, heterocyclylheterocyclylalkylamino,alkoxycarbonylheterocyclylamino, alkylaminocarbonyl, alkylcarbonylamino,hydrazinyl, alkylhydrazinyl, or carbocyclylhydrazinyl. Any substitutablemember of such group optionally is substituted with one or moresubstituents independently selected from the group consisting of alkyl,alkenyl, hydroxy, halogen, haloalkyl, alkoxy, haloalkoxy, keto, amino,nitro, cyano, alkylsulfonyl, alkylsulfinyl, alkylthio, alkoxyalkyl,carbocyclyloxy, heterocyclyl, and heterocyclylalkoxy.

In some preferred embodiments, R⁴ is hydroxy, alkylthio, alkylsulfinyl,alkylsulfonyl, carbocyclyloxy, carbocyclylalkoxy, carbocyclylthio,carbocyclylsulfinyl, carbocyclylsulfonyl, heterocyclylthio,heterocyclylsulfinyl, heterocyclylsulfonyl, carbocyclylalkoxy,heterocyclyloxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino,alkynylamino, carbocyclylamino, heterocyclylamino, alkoxy,alkoxyalkylamino, alkylaminoalkoxy, alkoxycarbonylamino,alkoxycarbocyclylamino, alkoxycarbocyclylalkylamino, aminosulfinyl,aminosulfonyl, alkylsulfonylamino, alkoxyalkoxy, aminoalkoxy,aminoalkylamino, alkylaminoalkylamino, carbocyclylalkylamino,alkylaminoalkylaminoalkylamino, alkylheterocyclylamino,heterocyclylalkylamino, alkylheterocyclylalkylamino,carbocyclylalkylheterocyclylamino, heterocyclylheterocyclylalkylamino,alkoxycarbonylheterocyclylamino, alkylcarbonylamino, hydrazinyl,alkylhydrazinyl, or carbocyclylhydrazinyl. Any substitutable member ofsuch group optionally is substituted with one or more substituentsindependently selected from the group consisting of alkyl, alkenyl,hydroxy, halogen, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro,cyano, alkylsulfonyl, alkylsulfinyl, alkylthio, alkoxyalkyl,carbocyclyloxy, heterocyclyl, and heterocyclylalkoxy.

In some preferred embodiments, R⁴ is hydroxy, carbocyclyloxy,carbocyclylalkoxy, carbocyclylalkoxy, heterocyclyloxy,heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino,carbocyclylamino, heterocyclylamino, alkoxy, alkoxyalkylamino,alkylaminoalkoxy, alkoxycarbonylamino, alkoxycarbocyclylamino,alkoxycarbocyclylalkylamino, alkylsulfonylamino, alkoxyalkoxy,aminoalkoxy, aminoalkylamino, alkylaminoalkylamino,carbocyclylalkylamino, alkylaminoalkylaminoalkylamino,alkylheterocyclylamino, heterocyclylalkylamino,alkylheterocyclylalkylamino, carbocyclylalkylheterocyclylamino,heterocyclylheterocyclylalkylamino, alkoxycarbonylheterocyclylamino,alkylcarbonylamino, hydrazinyl, alkylhydrazinyl, orcarbocyclylhydrazinyl. Any substitutable member of such group optionallyis substituted with one or more substituents independently selected fromthe group consisting of alkyl, alkenyl, hydroxy, halogen, haloalkyl,alkoxy, haloalkoxy, keto, amino, nitro, cyano, alkylsulfonyl,alkylsulfinyl, alkylthio, alkoxyalkyl, carbocyclyloxy, heterocyclyl, andheterocyclylalkoxy.

In some preferred embodiments, R⁴ is hydroxy, alkylthio,cyanocarbocyclyloxy, heterocyclyloxy, carbocyclylamino,dialkylaminoalkoxy, or dialkylaminoalkylamino.

In some preferred embodiments, R⁴ is alkylthio.

In some preferred embodiments, R⁴ is alkylsulfonyl.

In some preferred embodiments, R⁴ is hydrogen.

Specific examples of preferred compounds include those corresponding instructure to the following formulas:

B. Compound Preparation Process

The compound and salts of this invention can be prepared from materialsgenerally available in the art.

In a preferred embodiment, the synthesis begins by preparing a suitablyprotected ester of isonipecotic acid. The protecting group may, forexample, be a tert-butyloxycarbonyl radical (or “Boc”). TheBoc-protected isonipecotic acid ester may be prepared from acommercially available isonipecotate compound and di-t-butyldicarbonate:

Here, R^(A) may be, for example, C₁-C₆-alkyl, more preferably methyl orethyl, and even more preferably ethyl. Thus, for example, theBoc-protected isonipecotic acid ethyl ester may be prepared fromcommercially available ethyl isonipecotate and di-t-butyl dicarbonate:

The methyl ester similarly may be prepared from commercially availablemethyl isonipecotate and di-t-butyl dicarbonate.

The di-t-butyl dicarbonate is preferably charged to a reactor with fromabout 1.01 to about 1.05 mole equivalents of the isonipecotate in asuitable solvent. The solvent may be, for example, tetrahydrofuran(“THF”). While adding the isonipecotate, the temperature of theresulting mixture preferably is maintained at from about zero to about15° C. After all the isonipecotate has been added, the mixture ispreferably warmed to room temperature (i.e., from about 20 to about 25°C.) and agitated (e.g., stirred) for at least about 1 hour, morepreferably from about 1 to 3 hours, and even more preferably about 2hours. Afterward, the contents are preferably cooled to from about 0 toabout 10° C., more preferably to about 0° C., and the solvent isremoved. When the solvent is THF, it may be removed by, for example,vacuum distillation.

The protected isonipecotate may next be reacted with a suitablemethylheteroaryl to form a ketone:

Here, Y¹, Y², Y³, Y⁴, and Y⁵ are as defined above, except that if R⁴ isother than hydrogen, then the one of Y¹, Y², Y³, Y⁴, and Y⁵ that isdesired to be ═C(R⁴)— is, in some instances, preferably ═C(SCH₃)— atthis stage of the process. To illustrate, if it is desired to make asubstituted pyrazole wherein the substituent at the 4-position of thepyrazole is a pyrimidinyl group substituted at its 2-position, then themethylheteroaryl group would, in many instances, preferably be:

Before beginning this reaction, the methyl anion of the methylheteroarylpreferably is first prepared by treating the methylheteroaryl with fromabout 2.35 to about 2.49 mole equivalents, and more preferably about2.42 mole equivalents, of a base in the presence of an organic solvent(e.g., THF or ether, with THF being preferred) under nitrogen at areduced temperature (preferably from about zero to about 10° C., andmore preferably from about zero to about 5° C.). The base may be, forexample, lithium hexamethyldisilazide (“LiHMDS”), lithiumdiisopropylamide (“LDA”), or potassium tert-butoxide (“tBuOK”), withtBuOK being particularly preferred. From about 0.95 to about 1.03 moleequivalents, and more preferably about 0.95 mole equivalent, of theBoc-protected isonipecotate (based on moles of methylheteroaryl) is thenadded to the methyl anion mixture. The resulting mixture is agitated(e.g., stirred) for preferably at least about 2 hours, more preferablyfrom about 2 to about 4 hours, and even more preferably from about 3 toabout 4 hours, at a reduced temperature of from about 0 about 10° C.,more preferably from about 0 about 5° C., and even more preferably about5° C. The temperature of the mixture is then preferably increased tofrom about 5 to about 15° C., and more preferably to about 10° C., whereit is maintained for from about 0.8 to about 1.2 hours, and morepreferably about 1 hour, while the mixture continues to be agitated.

Impurities may be removed from the resulting ketone product mixtureusing acid/base extraction. In a preferred embodiment, from about 2.28to about 2.52 mole equivalents, and more preferably about 2.4 moleequivalents, of an acid solution (based on moles of Boc-protectedisonipecotate) is added to the reaction mixture while maintaining theinternal temperature at less than about 30° C. The acid may be, forexample, aqueous acetic acid. Following the addition of the acidsolution, the aqueous phase is removed (in, for example, a separatoryfunnel), and from about 0.23 to about 0.27 mole equivalents, and morepreferably about 0.25 mole equivalents, of a acid solution (based onmoles of Boc-protected isonipecotate) is then added to the organics. Theacid may be, for example, ammonium chloride or a dilute mineral acidsuch as 0.5 N hydrochloric acid. After the acid is added, the aqueousphase is preferably removed. The organic solvent may then be removedfrom the ketone product using, for example, distillation. If, forexample, the solvent is THF, it may be removed by slowly increasing thebatch temperature under vacuum (e.g., 200 torr) until it reaches fromabout 60 to about 65° C.

The ketone may next be reacted with toluenesulfonylhydrazide to form ahydrazone in a condensation reaction:

In a preferred embodiment, the ketone product is combined with asolvent, such as toluene, benzene, or THF, with toluene typically beingmore preferred. Various impurities that may be present in this mixture(e.g., isonipecotic acid and/or ammonium chloride) are preferablyremoved by adding water, agitating (e.g., stirring) the mixture for abrief period (e.g., 30 min), letting the mixture stand for a briefperiod (e.g., 1 hour), and then removing the aqueous layer. Theremaining organic layer is then combined with toluenesulfonylhydrazide.The mole ratio of toluenesulfonylhydrazide to protected isonipecotatereagent (used in the ketone-forming reaction) is preferably from about0.87 to about 0.93, and more preferably about 0.9.

After the toluenesulfonylhydrazide has been combined with the ketone,the mixture is preferably heated to a temperature of from about 66 toabout 74° C., and more preferably to about 70° C., while being agitated(e.g., stirred). This heating and agitation is preferably continued forfrom about 1.8 to about 2.2 hours, and more preferably about 2 hours.The mixture is preferably next refluxed at about 70° C. under reducedpressure (e.g., 200 torr) using, for example, a Dean Stark moisture trapfor from about 1.6 to about 2.4 hours, and more preferably 2 hours. Thebasic principles underlying the design of a Dean-Stark moisture trap arewell-known in the art and described in, for example, Dean, E. W. &Stark, D. D., “A Convenient Method for the Determination of Water inPetroleum and Other Organic Emulsions,” J. Indus. and Eng. Chem., Vol.12, No. 5. pp. 486-90 (May 1920) (incorporated herein by reference).

After the heating, the mixture is preferably cooled to from about −5 toabout 5° C., and more preferably about 0° C., over from about 1.2 toabout 1.8 and more preferably about 1.5 hours. The cooling is thenpreferably continued for from at least about 10 hours, and morepreferably at least about 12 hours.

After the cooling period, the solids are preferably separated (using,for example, filtration or centrifugation), washed with a solvent (e.g.,toluene, benzene, THF and/or ethyl acetate, and preferably ethylacetate), and then dried (e.g., under vacuum at an elevated temperatureof from about 25 to about 40° C., and more preferably about 40° C.).

The hydrazone may next be reacted with a suitable optionally-substitutedbenzoyl halide to form a protected pyrazole intermediate:

Here, R^(B) is halogen, preferably chloro.

In a preferred embodiment, the hydrazone is charged to a clean dryreactor (which preferably has been purged with nitrogen), along withfrom about 4.2:1 to about 4.8:1 (ml solvent:grams hydrazone solids, andmore preferably about 4.5:1 (ml solvent:grams hydrazone solids), of asolvent; from about 1.05 to about 1.68 mole equivalents, and morepreferably about 1.4 mole equivalents of a base (based on moles ofhydrazone); and from about 1.01 to about 1.25 mole equivalents, and morepreferably about 1.25 mole equivalents, of 4-chlorobenzoylchloride(based on moles of hydrazone). The solvent may be, for example, THF ortoluene. The base may be, for example, LiHMDS, LDA, tBuOK, ortriethylamine, with triethylamine being particularly preferred. Toenhance the rate of reaction, an activator of the4-chlorobenzoylchloride may be included in the reaction mixture as well.For example, about 0.1 mole equivalents of 4-N,N-dimethylaminopyridine(based on moles of hydrazone reagent) may be included. The4-chlorobenzoylchloride is preferably slowly charged to the reactorafter the hydrazone, solvent, base, and any activator have been charged.Once the 4-chlorobenzoylchloride has been charged, the reaction mixturepreferably is heated to a temperature of at least about 50° C., morepreferably greater than 50° C., even more preferably greater than 50° C.and no greater than about 65° C., and still even more preferably toabout 65° C. The heating is then preferably continued for greater than30 minutes, more preferably at least about 1 hour, even more preferablyfrom about 1 to about 2 hours, and still even more preferably about 2hours. The resulting product mixture is then preferably allowed to coolto room temperature.

It is particularly preferred to isolate the protected pyrazole productfrom the product mixture. Applicants have found, for example, that suchisolation generally improves product yield, purity, and reproducibilitydownstream. To remove existing salt impurities (and any other impuritiessoluble in water), water may be added to the product mixture. Theproduct mixture is preferably then agitated (e.g., stirred) for at leastabout 0.5 hours, more preferably from about 0.5 to about 1 hour, andeven more preferably about 0.5 hours. Phase separation is then allowedto occur, and the aqueous layer is removed. To remove impurities andcolor from the organics, an aqueous salt solution (approximately atleast about 25% (by weight), more preferably from about 3.5 to about3.88 mole equivalents (based on moles of hydrazone), and even morepreferably about 3.66 mole equivalents (based on moles of hydrazone))can subsequently (or alternatively) be added to the organic phase. Thesalt in the salt solution preferably does not exceed the saturationconcentration at room temperature. A particularly advantageous saltsolution is aqueous ammonium chloride. As with the water separation, thecombined salt solution and organics are agitated for from about 0.5 toabout 1 hour, and even more preferably about 0.5 hours. Phase separationis then allowed to occur, and the aqueous layer is removed. Theseparation may be conducted at room temperature.

Following phase separation to remove impurities, the protected pyrazoleintermediate preferably is precipitated out of the organic solvent. Thispreferably is achieved, at least in part, by using an anti-solvent. Ananti-solvent is a second solvent that, when mixed with a first solventcontaining a solubilized ingredient (in this case, the protectedpyrazole intermediate), causes that ingredient to be less soluble thanit is in the first solvent alone. The anti-solvent in this instance maybe, for example, a C₁-C₆ alcohol, preferably isopropyl alcohol (“IPA”).In a preferred embodiment, a preheated mixture (preferably at atemperature of greater than 25° C., more preferably at from about 50 toabout 60° C., and even more preferably at 55° C.) of IPA in water(preferably containing about 1:1 (vol:vol) IPA to water) is added to thereaction mixture (preferably after being pre-heated to a temperature ofgreater than 25° C., more preferably to from about 50 to about 60° C.,and even more preferably to about 55° C.) over a time period of at least1 hour, more preferably from about 1 to about 2 hours, and even morepreferably about 1 hour. After the addition is complete, the solution ispreferably agitated (e.g., stirred) at a temperature of greater than 25°C., more preferably from about 50 to about 60° C., and even morepreferably about 55° C., for at least about 3 hours, more preferablyfrom about 3 to about 5 hours, and even more preferably about 3 hours.The solution is then preferably cooled to a temperature of from about 20to about 28° C., and more preferably to about 25° C., at a rate of fromabout 0.1 to about 1° C. per minute, and more preferably at a rate ofabout 0.3° C. per minute. The slurry is then held at a temperature offrom about 20 to about 28° C., and more preferably about 25° C., for atleast about 2 hours, more preferably for from about 2 to about 24 hours,and even more preferably for about 2 hours. The precipitate is thenpreferably removed using, for example, filtration (with, for example, a4 micron filter cloth) or centrifugation. The solids are preferablywashed with additional anti-solvent and/or water, and dried. The solidsmay be dried using, for example, heat optionally under vacuum. If heatis used, the temperature is preferably from about 70 to about 80° C.,and more preferably about 80° C. The concentration of the protectedpyrazole intermediate in the cake preferably is greater than 30% (byweight), and in a particularly preferred embodiment is at least about50% (by weight), more preferably at least about 75% (by weight), evenmore preferably at least about 95% (by weight), still even morepreferably at least about 97% (by weight), and still yet even morepreferably at least about 98.5% (by weight).

Once isolated, the protected pyrazole intermediate preferably isde-protected to form a de-protected pyrazole intermediate (also referredto in this patent as an “unsubstituted piperidinyl intermediate”):

In a preferred embodiment, a reactor is first charged with the protectedpyrazole intermediate and a solvent to form a slurry. The slurrypreferably is agitated (e.g., stirred). The solvent may be, for example,water, THF, ethyl acetate, ethanol, butanol, isopropyl alcohol, acetone,or toluene, and preferably is THF or toluene. The amount of solventpreferably is at least about 1:1 (ml solvent:grams protected pyrazole),more preferably from about 2:1 to about 10:1 (ml solvent:grams protectedpyrazole), and even more preferably about 2.5:1 (ml solvent:gramsprotected pyrazole).

To de-protect the pyrazole intermediate, a base may be added to theslurry, typically in the presence of heat (preferably at a temperaturethat is greater than 25 and not greater than about 80° C.). In a morepreferred embodiment, however, an acid is used. In this embodiment, fromabout 2 to about 12 mole equivalents, and more preferably about 8.0 moleequivalents, of acid (based on moles of protected pyrazole intermediate)is slowly added to the mixture to remove the protecting groups of thepyrazole intermediate. Although many acids may be suitable, the acidpreferably has a pKa of no greater than about −3. In a particularlypreferred embodiment, the acid is HCl or H₂SO₄, with HCl generally beingmore preferred. If the acid comprises HCl, the solvent preferably istoluene. THF, for example, tends to react with HCl to form chlorobutylalcohol, which, in turn, acts as an alkylating agent that may formadditional impurities. In some preferred embodiments, the de-protectionreaction mixture is maintained at a temperature that is less than 65° C.In some such preferred embodiments, the reaction mixture is maintainedat a temperature of less than about 30° C., and more preferably at roomtemperature, for preferably at least about 1 hour. In some otherpreferred embodiments, the reaction mixture is maintained at atemperature of from about 25 to about 100° C., more preferably fromabout 65 to about 75° C., and even more preferably about 70° C., forfrom about 1.5 to about 3 hours, more preferably from about 2.0 to about2.5 hours, and even more preferably about 2 hours. After such heating,the mixture preferably is cooled to from about 20 to about 35° C., andmore preferably about 25° C.

As noted above, where the desired compound has a non-hydrogen R⁴substituent, it is often preferred that the carbon to be bonded to theR⁴ substituent be bonded to a methylthio group (“—SCH₃”) in themethylheteroaryl reagent (discussed above in connection with the ketonepreparation). In other words, the one of Y¹, Y², Y³, Y⁴, and Y⁵ that isdesired to be ═C(R⁴)— is preferably ═C(SCH₃)— (this is particularlypreferred where the desired R⁴ substituent is an amine or oxide). Ininstances where such a methylthio group is used, the above de-protectionprotocol is preferably modified to also displace the methylthio groupusing a suitable reagent for attaching the desired R⁴ substituent. Thus,for example, where R⁴ is at the two position of a pyrimidinyl group, theprotected pyrazole may be simultaneously de-protected while displacingthe methylthio group with the desired R⁴ substituent using the followinggeneral scheme:

As can be seen from this scheme, the methylthio group is preferablyfirst oxidized to methylsulfonyl with an oxidant (e.g., oxone®), H₂O₂,or 3-chloroperbenzoic acid (“mCPBA”)) in a suitable solvent, such asdichloromethane, acetonitrile, and/or tetrahydrofuran. After theoxidation, the methylsulfonyl group is preferably displaced with asuitable reagent (typically an amine or oxide) in a suitable solvent,such as tetrahydrofuran, dioxane, dimethylformamide, or acetontrile. Anoxide reagent can typically be generated from its respective alcoholwith a suitable base (e.g., LiHMDS, NaH, LDA, or tBuOK) in a suitablesolvent, such as tetrahydrofuran, dioxane, or dimethylformamide. Thedisplacement reaction preferably is conducted at a temperature of fromabout 20 to about 200° C. Under these conditions, the tosyl protectinggroup at the 1-position of the pyrazole typically will simultaneously bede-protected. The de-protection of the piperidinyl group maysubsequently be accomplished with trifluoroacetic acid or HCl in asolvent such as dichloromethane or dioxane. In a typically morepreferred embodiment, however, the de-protection of the piperidinylgroup is accomplished by using the de-protection protocol discussedabove for protected pyrazole intermediates generally.

Following the de-protection (including any displacement reaction), themajority of the pyrazole is in the aqueous phase of the mixture.Additional water is preferably added, and the resulting mixture isagitated (e.g., stirred) for from about 10 to about 60 minutes, and morepreferably about 20 minutes. The organics are then preferably removedfrom the aqueous layer. In a preferred embodiment, from about 7 to about9 mole equivalents, and more preferably about 8.2 mole equivalents, ofbase (based on moles of protected pyrazole intermediate) are then slowlyadded to the mixture until the pH is from about 11 to about 13, and morepreferably about 12.6. The base may be, for example, sodium acetate,potassium acetate, potassium hydroxide, and sodium hydroxide, withsodium hydroxide being preferred. After base addition is complete, themixture preferably is slowly heated to a temperature of greater than 25°C., more preferably to from about 65 to about 80° C., and even morepreferably to about 75° C. The heating is then preferably continued forat least about 1 hour, more preferably from about 1 to about 3 hours,even more preferably from about 1.5 to about 2 hours, and still evenmore preferably about 2 hours. The mixture preferably is subsequentlycooled to from about 0° C. to room temperature (more preferably to about2° C.) over from about 2 to about 5 hours (more preferably about 3hours), and then maintained at from about 0° C. to room temperature(more preferably about 2° C.) for from about 2 to about 6 hours (morepreferably about 4 hours). The precipitate may be collected using, forexample, filtration (with, for example, a 4 micron filter cloth) orcentrifugation. The resulting cake is preferably washed with deionizedwater (preferably a plurality of times) and acetonitrile. The cake maybe air-dried until a constant weight is achieved. If necessary, the cakemay alternatively (or additionally) be dried under vacuum at atemperature of from room temperature to about 70° C.

The de-protected pyrazole cake is preferably triturated withacetonitrile. This trituration tends to advantageously cause a polymorphtransformation that improves the physical characteristics of thede-protected pyrazole intermediate for downstream processes. In apreferred embodiment, acetonitrile is added to the de-protected pyrazolesolids in an amount such that the ratio of acetonitrile to solids is atleast about 4:1 (ml:grams), more preferably from about 3:1 to about 8:1(ml:grams), and even more preferably about 5:1 (ml:grams). The mixtureis then preferably heated to a temperature that is greater than 25° C.,more preferably to at least about 75° C., even more preferably to fromabout 80 to about 82° C., and still even more preferably to reflux. Thisheating preferably is continued for at least about 1 hour, morepreferably from about 1 to about 6 hours, and even more preferably about1 hour. The mixture is then preferably cooled to a temperature of nogreater than about 30° C., more preferably to from about 2 to about 20°C., even more preferably from about 2 to less than 20° C., and stilleven more preferably to about 5° C., for at least about 15 minutes, morepreferably from about 0.5 to about 2 hours, and even more preferably forabout 0.5 hour. The solids are then preferably collected using, forexample, filtration (with, for example, a 4 micron filter cloth) orcentrifugation. Afterward, the solids are preferably washed withacetonitrile, and then optionally dried. Drying may be achieved by, forexample, air drying to a constant weight or by heating the solids to atemperature of at least about 50° C., more preferably to from about 40to about 85° C., and even more preferably to about 85° C. This heatingmay optionally be conducted under a vacuum. The concentration ofde-protected in the resulting cake preferably is at least about 95% (byweight), more preferably at least about 96% (by weight), and even morepreferably at least about 99% (by weight).

The de-protected pyrazole intermediate is preferably reacted with aglycolic acid ester to form the desiredN-(2-hydroxyacetyl)-5-(4-piperidyl)pyrazole:

In a preferred embodiment, a solvate form of theN-(2-hydroxyacetyl)-5-(4-piperidyl)pyrazole product is formed. This isespecially preferable where theN-(2-hydroxyacetyl)-5-(4-piperidyl)pyrazole isN-(2-hydroxyacetyl)-5-(4-piperidyl)-4-(4-pyrimidinyl)-3-(4-chlorophenyl)pyrazole.As discussed below, the 1-methyl-2-pyrrolidinone(“N-methylpyrrolidinone” or “NMP”) solvate ofN-(2-hydroxyacetyl)-5-(4-piperidyl)-4-(4-pyrimidinyl)-3-(4-chlorophenyl)pyrazoleis often particularly preferred. In that instance, it is often alsopreferable to further convert the solvate into another crystalline form,particularly Form I crystallineN-(2-hydroxyacetyl)-5-(4-piperidyl)-4-(4-pyrimidinyl)-3-(4-chlorophenyl)pyrazole.

The glycolic acid ester preferably is C₁-C₆-alkyl glycolate (i.e., R^(C)in the above reaction is C₁-C₆-alkyl), more preferably ethyl glycolateor butyl glycolate, and even more preferably butyl glycolate. Thepreference for butyl glycolate stems from, for example, its low cost andthe fact that it has a boiling point that is above the preferredtemperature for the reaction.

The de-protected pyrazole is preferably charged to a reactor with about2.0 to about 8.0 mole equivalents, more preferably from about 2.0 toabout 3.0 mole equivalents, and even more preferably about 2.5 moleequivalents, of the glycolic acid ester in the presence of a solvent orwith neat glycolic acid ester (i.e., without a solvent). Where a solventis used, it preferably comprises a polar, aprotic solvent and/oralcohol. The solvent preferably is such that theN-(2-hydroxyacetyl)-5-(4-piperidyl)pyrazole is substantially soluble atelevated temperatures (e.g., at least about 60° C. for alcohols and 115°C. for aprotic solvents where theN-(2-hydroxyacetyl)-5-(4-piperidyl)pyrazole isN-(2-hydroxyacetyl)-5-(4-piperidyl)-4-(4-pyrimidinyl)-3-(4-chlorophenyl)pyrazole).The solubility of the N-(2-hydroxyacetyl)-5-(4-piperidyl) pyrazole atelevated temperatures is preferably sufficient to provide at least about10% (by weight) solution, more typically at least about 15% (by weight)solution, and even more typically at least about 20% (by weight)solution of N-(2-hydroxyacetyl)-5-(4-piperidyl)pyrazole in the solvent.The solubility of the N-(2-hydroxyacetyl)-5-(4-piperidyl) pyrazole atroom temperature is preferably less than about 5% (by weight) solution,more typically from about 0.1 to about 5% (by weight) solution, and evenmore typically from about 1 to about 3% (by weight) solution of theN-(2-hydroxyacetyl)-5-(4-piperidyl) pyrazole in the solvent. Suchsolvents include, for example, dimethylformamide (“DMF”) and/or NMP(particularly where the N-(2-hydroxyacetyl)-5-(4-piperidyl) pyrazole isN-(2-hydroxyacetyl)-5-(4-piperidyl)-4-(4-pyrimidinyl)-3-(4-chlorophenyl)pyrazole).Suitable solvents hypothetically also may include dimethylsulfoxide(“DMSO”). The preferred amount of solvent will vary from solvent tosolvent. Typically, from about 1:1 to about 8:1 (mL of solvent:gram ofde-protected pyrazole), more typically from about 2:1 to about 4:1(mL:g), and even more typically about 2:1 (mL:g) of the solvent arepreferably present. Generally, the preferred solvent is NMP. Thus, theremaining discussion will illustrate the invention using NMP as thesolvent.

The reaction may be conducted under standard peptide coupling conditionsas described in Schemes D-1 and D-2 and Example D-1 (Step 5) in PCTPublication No. WO 00/31063. In generally more preferred embodiments,however, the reaction is conducted in the presence of1,8-diazabicyclo[5.4.0]undec-7-ene (“DBU”) and/or1,5-diazabicyclo[4.3.0]non-5-ene, with1,8-diazabicyclo[5,4,0]undec-7-ene being particularly preferred. It ishypothesized that N,N,N′N′-tetraethyl-N″-cyclohexylguanidine mayalternatively be used. Preferably at least about 0.05 mole equivalents,more preferably from about 0.1 to about 0.4 mole equivalents, and evenmore preferably about 0.1 mole equivalents of the catalyst (preferably1,8-diazabicyclo[5,4,0]undec-7-ene) are present (based on moles ofde-protected pyrazole).

After charging the ingredients to the reactor, the resulting mixture ispreferably stirred while being heated to a temperature of greater than25° C., more preferably to at least about 60° C., even more preferablyto from about 90 to about 150° C., and still even more preferably toabout 110° C. The heating is preferably continued until no greater than5% (more preferably less than about 3%, and still more preferably lessthan about 0.5%) of the starting material remains in the reactionmixture. The amount of starting material may be detected in real timeusing, for example, liquid chromatographic analysis. Normally, theheating continues for at least about 2 hours, more typically from about2 to about 4 hours, even more typically for about 2 to about 3 hours,and still even more typically about 3 hours.

In many preferred embodiments, it is preferable to form a solvate of theN-(2-hydroxyacetyl)-5-(4-piperidyl) pyrazole. In such instances, themixture preferably is cooled to a temperature of no greater than about80° C., more preferably to from about 20° C. to about 60° C., and evenmore preferably to about 25° C. over a time period of at least about 30minutes, more preferably from about 1 to about 2 hours, and even morepreferably about 1 hour. After this initial cooling period, the mixtureis preferably cooled to a temperature of less than 20° C., morepreferably to from about 0 to about 5° C., and even more preferably toabout 0° C. over a time period of at least about 15 minutes, morepreferably from about 30 to about 60 minutes, and even more preferablyabout 30 minutes. This cooling is preferably continued for at leastabout 1 hour, more preferably from about 1 to about 2 hours, and evenmore preferably about 2 hours.

In a particularly preferred embodiment, an anti-solvent is added whilethe mixture is being cooled. In a particularly preferred embodiment, theanti-solvent is added to the mixture during the first cooling period,particularly at the end of the first cooling period. The anti-solventpreferably is a polar solvent, and may be, for example, water, ethylacetate, methanol, isopropyl alcohol, and/or ethanol, with ethanol beingparticularly preferred. Preferably, from about 0.2:1 to about 10:1 (mLof anti-solvent:grams de-protected pyrazole), more preferably from about0.2:1 to about 0.3:1 (mL:g), and even more preferably about 0.22 (mL:g)of anti-solvent are added. Where an anti-solvent is added, the coolingis preferably continued for from about 1 to about 6 hours, and morepreferably about 1 hour. The mixture then preferably is cooled furtherover from about 15 minutes to about 5 hour (more preferably about 30minutes) to a temperature of from about −5 to about 30° C. (morepreferably to from about 0 to about 2° C.), and maintained at thattemperature for from about 1 to about 24 hours, and more preferablyabout 2 hours.

The resulting solids are preferably collected via, for example,filtration (with, for example, 4 micron filter cloth) or centrifugation,washed at least once (preferably 2 times) with NMP and/or anti-solvent,and dried. The resulting cake preferably contains at least about 95% (byweight), more preferably at least about 98% (by weight), and even morepreferably at least about 99% by weight solvate. The amount of NMP toN-(2-hydroxyacetyl)-5-(4-piperidyl)pyrazole in the solvate is typicallyfrom less than about 200 ppm (or 0.02% (by weight)) to about a molarratio of about 1:1 (particularly where the solvate is an NMP solvate).

In many preferred embodiments where theN-(2-hydroxyacetyl)-5-(4-piperidyl) pyrazole isN-(2-hydroxyacetyl)-5-(4-piperidyl)-4-(4-pyrimidinyl)-3-(4-chlorophenyl)pyrazole,the NMP solvate is isolated and then converted to Form I crystallineN-(2-hydroxyacetyl)-5-(4-piperidyl)-4-(4-pyrimidinyl)-3-(4-chlorophenyl)pyrazole.

In a particularly preferred embodiment, the solvate is charged to areactor with a polar solvent. Such a solvent may be, for example, water,ethyl acetate, methanol, isopropyl alcohol, and/or ethanol, and ispreferably ethanol (particularly where ethanol was the anti-solventadded to the solvate mixture during cooling). Preferably, from about50:1 to about 5:1(ml solvent:gram NMP solvate solids), more preferablyfrom about 10:1 to about 8:1 (ml solvent:gram NMP solvate solids), andeven more preferably about 9:1 (ml solvent:gram NMP solvate solids). Inaddition to the solvent, from about 0.01 to about 0.4 equivalents, andmore preferably from about 0.12 to about 0.09 equivalents, of DBU (basedon moles of N-(2-hydroxyacetyl)-5-(4-piperidyl) pyrazole) may optionallybe charged to the reactor. The presence of this small amount of DBUtends to be, for example, advantageous for saponifying any bis-glycolateimpurity present in the mixture.

The solvate/solvent mixture preferably is heated to a temperature ofgreater than 25° C., more preferably to at least about 50° C., even morepreferably to from about 50 to about 80° C., and still even morepreferably to reflux. The heating is preferably continued for at least 1hour, more preferably from about 1 hour to about 5 hours, and still evenmore preferably about 4 hours. Although Applicants have found that 1hour is typically sufficient (particularly at reflux where ethanol isthe solvent) to convert the solvate to Form 1 crystallineN-(2-hydroxyacetyl)-5-(4-piperidyl)-4-(4-pyrimidinyl)-3-(4-chlorophenyl)pyrazole,Applicants have found that additional heating may often be advantageousfor obtaining a purer product.

Following the heating, the mixture preferably is cooled to a temperatureof less than 30° C., more preferably to from about 0 to about 30° C.,and even more preferably to about 15° C. over a time period of at leastabout 1 hour, more preferably from about 1.5 to about 5 hours, and evenmore preferably about 3 hours. Afterward, the solids are collectedusing, for example, filtration (preferably with a 4 micron filter cloth)or centrifugation. The cake is then preferably washed (preferably in adisplacement wash) at least once (and more preferably at least twice)with a polar solvent (preferably the solvent used during the reflux),and then dried. The cake preferably contains less than about 500 ppm ofNMP, more preferably less than 300 ppm of NMP, and even more preferablyless than 250 ppm of NMP.

C. Tautomeric Forms of the Compounds of this Invention

The present invention also is directed to the tautomeric forms ofcompounds of Formula (I). As illustrated below, the pyrazoles ofFormulas (A) and (B) are magnetically and structurally equivalentbecause of the prototropic tautomeric nature of the hydrogen:

D. Compounds of this Invention Having One or More Asymmetric Carbons

The present invention also comprises compounds of Formula (I) having oneor more asymmetric carbons. It is known to those skilled in the art thatthose pyrazoles of the present invention having asymmetric carbon atomsmay exist in diastereomeric, racemic, or optically active forms. All ofthese forms are contemplated within the scope of this invention. Morespecifically, the present invention includes enantiomers, diastereomers,racemic mixtures, and other mixtures thereof.

E. Salts of the Compounds of this Invention

The compounds of this invention may be used in the form of salts derivedfrom inorganic or organic acids. Depending on the particular compound(and/or its crystalline structure), a salt of the compound may beadvantageous due to one or more of the salt's physical properties, suchas enhanced pharmaceutical stability in differing temperatures andhumidities, or a desirable solubility in water or oil. In someinstances, a salt of a compound also may be used as an aid in theisolation, purification, and/or resolution of the compound.

Where a salt is intended to be administered to a patient (as opposed to,for example, being used in an in vitro context), the salt preferably ispharmaceutically-acceptable. Pharmaceutically-acceptable salts includesalts commonly used to form alkali metal salts and to form additionsalts of free acids or free bases. In general, these salts typically maybe prepared by conventional means with a compound of this invention byreacting, for example, the appropriate acid or base with the compound.

Pharmaceutically-acceptable acid addition salts of the compounds of thisinvention may be prepared from an inorganic or organic acid. Examples ofsuitable inorganic acids include hydrochloric, hydrobromic acid,hydroionic, nitric, carbonic, sulfuric, and phosphoric acid. Suitableorganic acids generally include, for example, aliphatic, cycloaliphatic,aromatic, araliphatic, heterocyclyl, carboxyic, and sulfonic classes oforganic acids. Specific examples of suitable organic acids includeacetate, trifluoroacetate, formate, propionate, succinate, glycolate,gluconate, digluconate, lactate, malate, tartaric acid, citrate,ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate,glutamate, benzoate, anthranilic acid, mesylate, stearate, salicylate,p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate),methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate,toluenesulfonate, 2-hydroxyethanesulfonate, sufanilate,cyclohexylaminosulfonate, algenic acid, b-hydroxybutyric acid,galactarate, galacturonate, adipate, alginate, bisulfate, butyrate,camphorate, camphorsulfonate, cyclopentanepropionate, dodecylsulfate,glycoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate,nicotinate, 2-naphthalesulfonate, oxalate, palmoate, pectinate,persulfate, 3-phenylpropionate, picrate, pivalate, thiocyanate,tosylate, and undecanoate.

Pharmaceutically-acceptable base addition salts of the compounds of thisinvention include, for example, metallic salts and organic salts.Preferred metallic salts include alkali metal (group Ia) salts, alkalineearth metal (group IIa) salts, and other physiological acceptable metalsalts. Such salts may be made from aluminum, calcium, lithium,magnesium, potassium, sodium, and zinc. Preferred organic salts may bemade from tertiary amines and quaternary amine salts, such astromethamine, diethylamine, N,N′-dibenzylethylenediamine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine(N-methylglucamine), and procaine. Basic nitrogen-containing groups maybe quaternized with agents such as lower alkyl (C₁-C₆) halides (e.g.,methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides),dialkyl sulfates (e.g., dimethyl, diethyl, dibuytl, and diamylsulfates), long chain halides (e.g., decyl, lauryl, myristyl, andstearyl chlorides, bromides, and iodides), arylalkyl halides (e.g.,benzyl and phenethyl bromides), and others.

Particularly preferred salts of the compounds of this invention includehydrochloric acid (HCl) salts, trifluoroacetate (CF₃COOH or “TFA”)salts, mesylate salts, and tosylate salts.

F. Preventing or Treating Conditions Using the Compounds Prepared bythis Invention

This invention is directed, in part, to a method for preventing ortreating a condition (typically a pathological condition) in a mammal(e.g., a human, companion animal, farm animal, laboratory animal, zooanimal, or wild animal) having or disposed to having such a condition.

Some embodiments of this invention are directed to a method forpreventing or treating a p38-mediated condition. As used herein, theterm “p38-mediated condition” refers to any condition (particularlypathological conditions, i.e., diseases and disorders) in which p38kinase (particularly p38α kinase) plays a role, either by control of p38kinase itself, or by p38 kinase causing another factor to be released,such as, for example, IL-1, IL-6, or IL-8. A disease state in which, forinstance, IL-1 is a major component, and whose production or action isexacerbated or secreted in response to p38, would therefore beconsidered a disorder mediated by p38.

The compounds of this invention generally tend to be useful for treatingor preventing pathological conditions that include, but are not limitedto:

-   -   (a) inflammation;    -   (b) arthritis, such as rheumatoid arthritis,        spondyloarthropathies, gouty arthritis, osteoarthritis, systemic        lupus erythematosus arthritis, juvenile arthritis,        osteoarthritis, and gouty arthritis;    -   (c) neuroinflammation;    -   (d) pain (i.e., use of the compounds as analgesics), such as        neuropathic pain;    -   (e) fever (i.e., use of the compounds as antipyretics);    -   (f) pulmonary disorders or lung inflammation, such as adult        respiratory distress syndrome, pulmonary sarcoisosis, asthma,        silicosis, and chronic pulmonary inflammatory disease;    -   (g) cardiovascular diseases, such as atherosclerosis, myocardial        infarction (such as post-myocardial infarction indications),        thrombosis, congestive heart failure, cardiac reperfusion        injury, and complications associated with hypertension and/or        heart failure such as vascular organ damage;    -   (h) cardiomyopathy;    -   (i) stroke, such as ischemic and hemorrhagic stroke;    -   (j) ischemia, such as brain ischemia and ischemia resulting from        cardiac/coronary bypass;    -   (k) reperfusion injury;    -   (l) renal reperfusion injury;    -   (m) brain edema;    -   (n) neurotrauma and brain trauma, such as closed head injury;    -   (o) neurodegenerative disorders;    -   (p) central nervous system disorders (these include, for        example, disorders having an inflammatory or apoptotic        component), such as Alzheimer's disease, Parkinson's disease,        Huntington's Disease, amyotrophic lateral sclerosis, spinal cord        injury, and peripheral neuropathy;    -   (q) liver disease and nephritis;    -   (r) gastrointestinal conditions, such as inflammatory bowel        disease, Crohn's disease, gastritis, irritable bowel syndrome,        and ulcerative colitis;    -   (s) ulcerative diseases, such as gastric ulcer;    -   (t) ophthalmic diseases, such as retinitis, retinopathies (such        as diabetic retinopathy), uveitis, ocular photophobia,        nonglaucomatous optic nerve atrophy, and age-related macular        degeneration (ARMD) (such as ARMD-atrophic form);    -   (u) ophthalmological conditions, such as corneal graft        rejection, ocular neovascularization, retinal neovascularization        (such as neovascularization following injury or infection), and        retrolental fibroplasia;    -   (v) glaucoma, such as primary open angle glaucoma (POAG),        juvenile onset primary open-angle glaucoma, angle-closure        glaucoma, pseudoexfoliative glaucoma, anterior ischemic optic        neuropathy (AION), ocular hypertension, Reiger's syndrome,        normal tension glaucoma, neovascular glaucoma, ocular        inflammation, and corticosteroid-induced glaucoma;    -   (w) acute injury to the eye tissue and ocular traumas, such as        post-traumatic glaucoma, traumatic optic neuropathy, and central        retinal artery occlusion (CRAO);    -   (x) diabetes;    -   (y) diabetic nephropathy;    -   (z) skin-related conditions, such as psoriasis, eczema, bums,        dermatitis, keloid formation, scar tissue formation, and        angiogenic disorders;    -   (aa) viral and bacterial infections, such as sepsis, septic        shock, gram negative sepsis, malaria, meningitis, opportunistic        infections, cachexia secondary to infection or malignancy,        cachexia secondary to acquired immune deficiency syndrome        (AIDS), AIDS, ARC (AIDS related complex), pneumonia, and herpes        virus;    -   (bb) myalgias due to infection;    -   (cc) influenza;    -   (dd) endotoxic shock;    -   (ee) toxic shock syndrome;    -   (ff) autoimmune disease, such as graft vs. host reaction and        allograft rejections;    -   (gg) bone resorption diseases, such as osteoporosis;    -   (hh) multiple sclerosis;    -   (ii) disorders of the female reproductive system, such as        endometriosis;    -   (jj) pathological, but non-malignant, conditions, such as        hemaginomas (such as infantile hemaginomas), angiofibroma of the        nasopharynx, and avascular necrosis of bone;    -   (kk) benign and malignant tumors/neoplasia including cancer,        such as colorectal cancer, brain cancer, bone cancer, epithelial        cell-derived neoplasia (epithelial carcinoma) such as basal cell        carcinoma, adenocarcinoma, gastrointestinal cancer such as lip        cancer, mouth cancer, esophageal cancer, small bowel cancer and        stomach cancer, colon cancer, liver cancer, bladder cancer,        pancreas cancer, ovarian cancer, cervical cancer, lung cancer,        breast cancer, skin cancer such as squamus cell and basal cell        cancers, prostate cancer, renal cell carcinoma, and other known        cancers that affect epithelial cells throughout the body;    -   (ll) leukemia;    -   (mm) lymphoma, such as B cell lymphoma;    -   (nn) systemic lupus erthrematosis (SLE);    -   (oo) angiogenesis including neoplasia; and    -   (pp) metastasis.

Some embodiments of this invention are alternatively (or additionally)directed to a method for preventing or treating a TNF-mediatedcondition. As used herein, the term “TNF-mediated condition” refers toany condition (particularly any pathological conditions, i.e., diseasesor disorders) in which TNF plays a role, either by control of TNFitself, or by TNF causing another monokine to be released, such as, forexample, IL-1, IL-6, and/or IL-8. A disease state in which, forinstance, IL-1 is a major component and whose production or action isexacerbated or secreted in response to TNF, would therefore beconsidered a disorder mediated by TNF.

Examples of TNF-mediated conditions include inflammation (e.g.,rheumatoid arthritis), autoimmune disease, graft rejection, multiplesclerosis, a fibrotic disease, cancer, an infectious disease (e.g.,malaria, mycobacterial infection, meningitis, etc.), fever, psoriasis, acardiovascular disease (e.g., post-ischemic reperfusion injury andcongestive heart failure), a pulmonary disease, hemorrhage, coagulation,hyperoxic alveolar injury, radiation damage, acute phase responses likethose seen with infections and sepsis and during shock (e.g., septicshock, hemodynamic shock, etc.), cachexia, and anorexia. Such conditionsalso include infectious diseases. Such infectious diseases include, forexample, malaria, mycobacterial infection, meningitis. Such infectiousdiseases also include viral infections, such as HIV, influenza virus,and herpes virus, including herpes simplex virus type-1 (HSV-1), herpessimplex virus type-2 (HSV-2), cytomegalovirus (CMV), varicella-zostervirus (VZV), Epstein-Barr virus, human herpesvirus-6 (HHV-6), humanherpesvirus-7 (HHV-7), human herpesvirus-8 (HHV-8), pseudorabies andrhinotracheitis, among others.

As TNF-β has close structural homology with TNF-α (also known ascachectin), and because each induces similar biologic responses andbinds to the same cellular receptor, the synthesis of both TNF-α andTNF-β tend to be inhibited by the compounds of this invention and thusare herein referred to collectively as “TNF” unless specificallydelineated otherwise.

Some embodiments of this invention are alternatively (or additionally)directed to a method for preventing or treating acyclooxygenase-2-mediated condition. As used herein, the term“cyclooxygenase-2-mediated condition” refers to any condition(particularly pathological conditions, i.e., diseases and disorders) inwhich cyclooxygenase-2 plays a role, either by control ofcyclooxygenase-2 itself, or by cyclooxygenase-2 causing another factorto be released. Many cyclooxygenase-2-mediated conditions are known inthe art, and include, for example, inflammation and othercyclooxygenase-mediated disorders listed by Carter et al. in U.S. Pat.No. 6,271,253.

In some embodiments of particular interest, the condition treated orprevented by the methods of this invention comprises inflammation.

In some embodiments of particular interest, the condition treated orprevented by the methods of this invention comprises arthritis.

In some embodiments of particular interest, the condition treated orprevented by the methods of this invention comprises rheumatoidarthritis.

In some embodiments of particular interest, the condition treated orprevented by the methods of this invention comprises asthma.

In some embodiments of particular interest, the condition treated orprevented by the methods of this invention comprises a coronarycondition.

In some embodiments of particular interest, the condition treated orprevented by the methods of this invention comprises bone loss.

In some embodiments of particular interest, the condition treated orprevented by the methods of this invention comprises B cell lymphoma.

The phrase “preventing a condition” means reducing the risk of (ordelaying) the onset of the condition in a mammal that does not have thecondition, but is predisposed to having the condition. In contrast, thephrase “treating a condition” means ameliorating, suppressing, oreradicating an existing condition.

A wide variety of methods may be used alone or in combination toadminister the pyrazole compounds described above. For example, thecompounds may be administered orally, intravascularly (IV),intraperitoneally, subcutaneously, intramuscularly (IM), by inhalationspray, rectally, or topically.

Typically, a compound described in this specification is administered inan amount effective to inhibit p38 kinase (particularly p38α kinase),TNF (particularly TNF-α), and/or cyclooxygenase (particularlycyclooxygenase-2). The preferred total daily dose of the pyrazolecompound (administered in single or divided doses) is typically fromabout 0.01 to about 100 mg/kg, more preferably from about 0.1 to about50 mg/kg, and even more preferably from about 0.5 to about 30 mg/kg(i.e., mg pyrazole compound per kg body weight). Dosage unitcompositions may contain such amounts or submultiples thereof to make upthe daily dose. In many instances, the administration of the compoundwill be repeated a plurality of times in a day (typically no greaterthan 4 times). Multiple doses per day typically may be used to increasethe total daily dose, if desired.

Factors affecting the preferred dosage regimen include the type, age,weight, sex, diet, and condition of the patient; the severity of thepathological condition; the route of administration; pharmacologicalconsiderations, such as the activity, efficacy, pharmacokinetic, andtoxicology profiles of the particular pyrazole compound employed;whether a drug delivery system is utilized; and whether the pyrazolecompound is administered as part of a drug combination. Thus, the dosageregimen actually employed can vary widely, and, therefore, can deviatefrom the preferred dosage regimen set forth above.

The present compounds may be used in co-therapies, partially orcompletely, in place of other conventional anti-inflammatory, such astogether with steroids, cyclooxygenase-2 inhibitors, non-steroidalanti-inflammatory drugs (“NSAIDs”), disease-modifying anti-rheumaticdrugs (“DMARDs”), immunosuppressive agents, 5-lipoxygenase inhibitors,leukotriene B4 (“LTB4”) antagonists, and leukotriene A4 (“LTA4”)hydrolase inhibitors.

G. Pharmaceutical Compositions Containing the Compounds Prepared by thisInvention

This invention also is directed to pharmaceutical compositions (or“medicaments”) comprising the substituted pyrazoles described above(including tautomers of the compounds, and pharmaceutically-acceptablesalts of the compounds and tautomers), and to methods for makingpharmaceutical compositions comprising those compounds in combinationwith one or more conventional non-toxic, pharmaceutically-acceptablecarriers, diluents, wetting or suspending agents, vehicles, and/oradjuvants (the carriers, diluents, wetting or suspending agents,vehicles, and adjuvants sometimes being collectively referred to in thisspecification as “carrier materials”); and/or other active ingredients.The preferred composition depends on the method of administration.Formulation of drugs is generally discussed in, for example, Hoover,John E., Remington's Pharmaceutical Sciences (Mack Publishing Co.,Easton, Pa.: 1975) (incorporated by reference into this specification).See also, Liberman, H. A., Lachman, L., eds., Pharmaceutical DosageForms (Marcel Decker, New York, N.Y., 1980) (incorporated by referenceinto this specification). In many preferred embodiments, thepharmaceutical composition is made in the form of a dosage unitcontaining a particular amount of the active ingredient. Typically, thepharmaceutical composition contains from about 0.1 to 1000 mg (and moretypically, 7.0 to 350 mg) of the substituted pyrazole.

Solid dosage forms for oral administration include, for example, hard orsoft capsules, tablets, pills, powders, and granules. In such soliddosage forms, the substituted pyrazoles are ordinarily combined with oneor more adjuvants. If administered per os, the substituted pyrazoles maybe mixed with lactose, sucrose, starch powder, cellulose esters ofalkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesiumstearate, magnesium oxide, sodium and calcium salts of phosphoric andsulfuric acids, gelatin, acacia gum, sodium alginate,polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted orencapsulated for convenient administration. Such capsules or tablets maycontain a controlled-release formulation, as may be provided in adispersion of the compound of this invention in hydroxypropylmethylcellulose. In the case of capsules, tablets, and pills, the dosage formsalso may comprise buffering agents, such as sodium citrate, or magnesiumor calcium carbonate or bicarbonate. Tablets and pills additionally maybe prepared with enteric coatings.

Liquid dosage forms for oral administration include, for example,pharmaceutically-acceptable emulsions, solutions, suspensions, syrups,and elixirs containing inert diluents commonly used in the art (e.g.,water). Such compositions also may comprise adjuvants, such as wetting,emulsifying, suspending, flavoring (e.g., sweetening), and/or perfumingagents.

“Parenteral administration” includes subcutaneous injections,intravenous injections, intramuscular injections, intrastemalinjections, and infusion. Injectable preparations (e.g., sterileinjectable aqueous or oleaginous suspensions) may be formulatedaccording to the known art using suitable dispersing, wetting agents,and/or suspending agents. Acceptable carrier materials include, forexample, water, 1,3-butanediol, Ringer's solution, isotonic sodiumchloride solution, bland fixed oils (e.g., synthetic mono- ordiglycerides), dextrose, mannitol, fatty acids (e.g., oleic acid),dimethyl acetamide, surfactants (e.g., ionic and non-ionic detergents),and/or polyethylene glycols (e.g., PEG 400).

Formulations for parenteral administration may, for example, be preparedfrom sterile powders or granules having one or more of the carriersmaterials mentioned for use in the formulations for oral administration.The substituted pyrazoles may be dissolved in water, polyethyleneglycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil,sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. ThepH may be adjusted, if necessary, with a suitable acid, base, or buffer.

The compounds of this invention preferably make up from about 0.075 toabout 30% (w/w) (more preferably 0.2 to 20% (w/w), and even morepreferably 0.4 to 15% (w/w)) of a pharmaceutical composition used fortopical or rectal administration.

Suppositories for rectal administration may be prepared by, for example,mixing a compound of this invention with a suitable nonirritatingexcipient that is solid at ordinary temperatures, but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Suitable excipients include, for example, such as cocoa butter;synthetic mono-, di-, or triglycerides; fatty acids; and/or polyethyleneglycols.

“Topical administration” includes transdermal administration, such asvia transdermal patches or iontophoresis devices. Compositions fortopical administration also include, for example, topical gels, sprays,ointments, and creams.

When formulated in an ointment, the compounds of this invention may beemployed with, for example, either a paraffinic or a water-miscibleointment base. When formulated in a cream, the active ingredient(s) maybe formulated with, for example, an oil-in-water cream base. If desired,the aqueous phase of the cream base may include, for example at leastabout 30% (w/w) of a polyhydric alcohol, such as propylene glycol,butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol, andmixtures thereof.

A topical formulation may include a compound which enhances absorptionor penetration of the active ingredient through the skin or otheraffected areas. Examples of such dermal penetration enhancers includedimethylsulfoxide and related analogs.

When the compounds of this invention are administered by a transdermaldevice, administration will be accomplished using a patch either of thereservoir and porous membrane type or of a solid matrix variety. Ineither case, the active agent is delivered continuously from thereservoir or microcapsules through a membrane into the active agentpermeable adhesive, which is in contact with the skin or mucosa of therecipient. If the active agent is absorbed through the skin, acontrolled and predetermined flow of the active agent is administered tothe recipient. In the case of microcapsules, the encapsulating agent mayalso function as the membrane. The transdermal patch may include thecompound in a suitable solvent system with an adhesive system, such asan acrylic emulsion, and a polyester patch. The oily phase of theemulsions of this invention may be constituted from known ingredients ina known manner. While the phase may comprise merely an emulsifier, itmay comprise, for example, a mixture of at least one emulsifier with afat or an oil or with both a fat and an oil. Preferably, a hydrophilicemulsifier is included together with a lipophilic emulsifier which actsas a stabilizer. It is also preferable to include both an oil and a fat.Together, the emulsifier(s) with or without stabilizer(s) make-up theso-called emulsifying wax, and the wax together with the oil and fatmake up the so-called emulsifying ointment base which forms the oilydispersed phase of the cream formulations. Emulsifiers and emulsionstabilizers suitable for use in the formulation of the present inventioninclude Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol,glyceryl monostearate, and sodium lauryl sulfate, among others. Thechoice of suitable oils or fats for the formulation is based onachieving the desired cosmetic properties, given that the solubility ofthe active compound in most oils likely to be used in pharmaceuticalemulsion formulations is very low. Thus, the cream should preferably bea non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters, for example,may be used. These may be used alone or in combination depending on theproperties required. Alternatively, high melting point lipids such aswhite soft paraffin and/or liquid paraffin or other mineral oils may beused. Formulations suitable for topical administration to the eye alsoinclude eye drops wherein the compound of this invention is dissolved orsuspended in suitable carrier, typically comprising an aqueous solvent.The compounds of this invention are preferably present in suchformulations in a concentration of from about 0.5 to about 20% (w/w)(more preferably 0.5 to 10% (w/w), and often even more preferably about1.5% (w/w)).

Other carrier materials and modes of administration known in thepharmaceutical art may also be used.

H. Definitions

The term “alkyl” (alone or in combination with another term(s)) means astraight-or branched-chain saturated hydrocarbyl substituent (i.e., asubstituent containing only carbon and hydrogen) typically containingfrom 1 to about 20 carbon atoms, more typically from 1 to about 12carbon atoms, even more typically from 1 to about 8 carbon atoms, andstill even more typically from 1 to about 6 carbon atoms. Examples ofsuch substituents include methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, and octyl.

The term “alkenyl” (alone or in combination with another term(s)) meansa straight- or branched-chain hydrocarbyl substituent containing one ormore double bonds and typically from 2 to about 20 carbon atoms, moretypically from 2 to about 12 carbon atoms, even more typically from 2 toabout 8 carbon atoms, and still even more typically from 2 to about 6carbon atoms. Examples of such substituents include ethenyl (vinyl);2-propenyl; 3-propenyl; 1,4-pentadienyl; 1,4-butadienyl; 1-butenyl;2-butenyl; 3-butenyl; and decenyl.

The term “alkynyl” (alone or in combination with another term(s)) meansa straight- or branched-chain hydrocarbyl substituent containing one ormore triple bonds and typically from 2 to about 20 carbon atoms, moretypically from 2 to about 12 carbon atoms, even more typically from 2 toabout 8 carbon atoms, and still even more typically from 2 to about 6carbon atoms. Examples of such substituents include ethynyl, 1-propynyl,2-propynyl, decynyl, 1-butynyl, 2-butynyl, 3-butynyl, and 1-pentynyl.

The term “carbocyclyl” (alone or in combination with another term(s))means a saturated cyclic (i.e., “cycloalkyl”), partially saturatedcyclic (i.e., “cycloalkenyl”), or completely unsaturated (i.e., “aryl”)hydrocarbyl substituent containing from 3 to 14 carbon ring atoms (“ringatoms” are the atoms bound together to form the ring or rings of acyclic substituent). A carbocyclyl may be a single ring, which typicallycontains from 3 to 6 ring atoms. Examples of such single-ringcarbocyclyls include cyclopropanyl, cyclobutanyl, cyclopentyl,cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl,cyclohexadienyl, and phenyl. A carbocyclyl alternatively may be 2 or 3rings fused together, such as naphthalenyl, tetrahydronaphthalenyl (alsoknown as “tetralinyl”), indenyl, isoindenyl, indanyl, bicyclodecanyl,anthracenyl, phenanthrene, benzonaphthenyl (also known as “phenalenyl”),fluoreneyl, decalinyl, and norpinanyl.

The term “cycloalkyl” (alone or in combination with another term(s))means a saturated carbocyclyl substituent containing from 3 to about 14carbon ring atoms, more typically from 3 to about 12 carbon ring atoms,and even more typically from 3 to about 8 carbon ring atoms. Acycloalkyl may be a single carbon ring, which typically contains from 3to 6 carbon ring atoms. Examples of single-ring cycloalkyls includecyclopropyl (or “cyclopropanyl”), cyclobutyl (or “cyclobutanyl”),cyclopentyl (or “cyclopentanyl”), and cyclohexyl (or “cyclohexanyl”). Acycloalkyl alternatively may be 2 or 3 carbon rings fused together, suchas, for example, decalinyl or norpinanyl.

The term “cycloalkylalkyl” (alone or in combination with anotherterm(s)) means alkyl substituted with cycloalkyl. Examples of suchsubstituents include cyclopropylmethyl, cyclobutylmethyl,cyclopentylmethyl, and cyclohexylmethyl.

The term “cycloalkenyl” (alone or in combination with another term(s))means a partially unsaturated carbocyclyl substituent. Examples of suchsubstituents include cyclobutenyl, cyclopentenyl, and cyclohexenyl.

The term “aryl” (alone or in combination with another term(s)) means anaromatic carbocyclyl containing from 6 to 14 carbon ring atoms. Examplesof aryls include phenyl, naphthalenyl, and indenyl.

In some instances, the number of carbon atoms in a hydrocarbylsubstituent (e.g., alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,aryl, etc.) is indicated by the prefix “C_(x)-C_(y)-”, wherein x is theminimum and y is the maximum number of carbon atoms in the substituent.Thus, for example, “C₁-C₆-alkyl” refers to an alkyl substituentcontaining from 1 to 6 carbon atoms. Illustrating further,C₃-C₆-cycloalkyl means a saturated carbocyclyl containing from 3 to 6carbon ring atoms.

The term “arylalkyl” (alone or in combination with another term(s))means alkyl substituted with aryl.

The term “benzyl” (alone or in combination with another term(s)) means amethyl radical substituted with phenyl, i.e., the following structure:

The term “benzene” means the following structure:

The term “hydrogen” (alone or in combination with another term(s)) meansa hydrogen radical, and may be depicted as —H.

The term “hydroxy” or “hydroxyl” (alone or in combination with anotherterm(s)) means —OH.

The term “hydroxyalkyl” (alone or in combination with another term(s))means alkyl substituted with one more hydroxy.

The term “nitro” (alone or in combination with another term(s)) means—NO₂.

The term “cyano” (alone or in combination with another term(s)) means—CN, which also may be depicted:

The term “keto” (alone or in combination with another term(s)) means anoxo radical, and may be depicted as ═O.

The term “carboxy” or “carboxyl” (alone or in combination with anotherterm(s)) means —C(O)—OH, which also may be depicted as:

The term “amino” (alone or in combination with another term(s)) means—NH₂. The term “monosubstituted amino” (alone or in combination withanother term(s)) means an amino substituent wherein one of the hydrogenradicals is replaced by a non-hydrogen substituent. The term“disubstituted amino” (alone or in combination with another term(s))means an amino substituent wherein both of the hydrogen atoms arereplaced by non-hydrogen substituents, which may be identical ordifferent.

The term “halogen” (alone or in combination with another term(s)) meansa fluorine radical (which may be depicted as —F), chlorine radical(which may be depicted as —Cl), bromine radical (which may be depictedas —Br), or iodine radical (which may be depicted as —I). Typically, afluorine radical or chlorine radical is preferred, with a fluorineradical often being particularly preferred.

The prefix “halo” indicates that the substituent to which the prefix isattached is substituted with one or more independently selected halogenradicals. For example, haloalkyl means an alkyl substituent wherein atleast one hydrogen radical is replaced with a halogen radical. Wherethere are more than one hydrogens replaced with halogens, the halogensmay be the identical or different. Examples of haloalkyls includechloromethyl, dichloromethyl, difluorochloromethyl,dichlorofluoromethyl, trichloromethyl, 1-bromoethyl, fluoromethyl,difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, difluoroethyl,pentafluoroethyl, difluoropropyl, dichloropropyl, and heptafluoropropyl.Illustrating further, “haloalkoxy” means an alkoxy substituent whereinat least one hydrogen radical is replaced by a halogen radical. Examplesof haloalkoxy substituents include chloromethoxy, 1-bromoethoxy,fluoromethoxy, difluoromethoxy, trifluoromethoxy (also known as“perfluoromethyloxy”), and 1,1,1,-trifluoroethoxy. It should berecognized that if a substituent is substituted by more than one halogenradical, those halogen radicals may be identical or different (unlessotherwise stated).

The term “carbonyl” (alone or in combination with another term(s)) means—C(O)—, which also may be depicted as:

This term also is intended to encompass a hydrated carbonyl substituent,i.e., —C(OH)₂—.

The term “aminocarbonyl” (alone or in combination with another term(s))means —C(O)—NH₂, which also may be depicted as:

The term “oxy” (alone or in combination with another term(s)) means anether substituent, and may be depicted as —O—.

The term “alkoxy” (alone or in combination with another term(s)) meansan alkylether substituent, i.e., —O-alkyl. Examples of such asubstituent include methoxy (—O—CH₃), ethoxy, n-propoxy, isopropoxy,n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy.

The term “alkylthio” (alone or in combination with another term(s))means —S-alkyl. For example, “methylthio” is —S—CH₃. Other examples ofalkylthio substituents include ethylthio, propylthio, butylthio, andhexylthio.

The term “alkylcarbonyl” or “alkanoyl” (alone or in combination withanother term(s)) means —C(O)-alkyl. For example, “ethylcarbonyl” may bedepicted as:

Examples of other often preferred alkylcarbonyl substituents includemethylcarbonyl, propylcarbonyl, butylcarbonyl, pentylcarbonyl, andhexylcarbonyl.

The term “aminoalkylcarbonyl” (alone or in combination with anotherterm(s)) means —C(O)-alkyl-NH₂. For example, “aminomethylcarbonyl” maybe depicted as:

The term “alkoxycarbonyl” (alone or in combination with another term(s))means —C(O)—O-alkyl. For example, “ethoxycarbonyl” may be depicted as:

Examples of other often preferred alkoxycarbonyl substituents includemethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl,pentoxycarbonyl, and hexyloxycarbonyl.

The term “carbocyclylcarbonyl” (alone or in combination with anotherterm(s)) means —C(O)-carbocyclyl. For example, “phenylcarbonyl” may bedepicted as:

Similarly, the term “heterocyclylcarbonyl” (alone or in combination withanother term(s)) means —C(O)-heterocyclyl.

The term “heterocyclylalkylcarbonyl” (alone or in combination withanother term(s)) means —C(O)-alkyl-heterocyclyl.

The term “carbocyclyloxycarbonyl” (alone or in combination with anotherterm(s)) means —C(O)—O-carbocyclyl. For example, “phenyloxycarbonyl” maybe depicted as:

The term “carbocyclylalkoxycarbonyl” (alone or in combination withanother term(s)) means —C(O)—O-alkyl-carbocyclyl. For example,“phenylethoxycarbonyl” may be depicted as:

The term “thio” or “thia” (alone or in combination with another term(s))means a thiaether substituent, i.e., an ether substituent wherein adivalent sulfur atom is in the place of the ether oxygen atom. Such asubstituent may be depicted as —S—. This, for example,“alkyl-thio-alkyl” means alkyl-S-alkyl.

The term “thiol” (alone or in combination with another term(s)) means asulfhydryl substituent, and may be depicted as —SH.

The term “sulfonyl” (alone or in combination with another term(s)) means—S(O)₂—, which also may be depicted as:

Thus, for example, “alkyl-sulfonyl-alkyl” means alkyl-S(O)₂-alkyl.Examples of typically preferred alkylsulfonyl substituents includemethylsulfonyl, ethylsulfonyl, and propylsulfonyl.

The term “aminosulfonyl” (alone or in combination with another term(s))means —S(O)₂—NH₂, which also may be depicted as:

The term “sulfinyl” or “sulfoxido” (alone or in combination with anotherterm(s)) means —S(O)—, which also may be depicted as:

Thus, for example, “alkylsulfinylalkyl” or “alkylsulfoxidoalkyl” meansalkyl-S(O)-alkyl. Typically preferred alkylsulfinyl groups includemethylsulfinyl, ethylsulfinyl, butylsulfinyl, and hexylsulfinyl.

The term “heterocyclyl” (alone or in combination with another term(s))means a saturated (i.e., “heterocycloalkyl”), partially saturated (i.e.,“heterocycloalkenyl”), or completely unsaturated (i.e., “heteroaryl”)ring structure containing a total of 3 to 14 ring atoms. At least one ofthe ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), withthe remaining ring atoms being independently selected from the groupconsisting of carbon, oxygen, nitrogen, and sulfur.

A heterocyclyl may be a single ring, which typically contains from 3 to7 ring atoms, more typically from 3 to 6 ring atoms, and even moretypically 5 to 6 ring atoms. Examples of single-ring heterocyclylsinclude furanyl, dihydrofurnayl, tetradydrofurnayl, thiophenyl (alsoknown as “thiofuranyl”), dihydrothiophenyl, tetrahydrothiophenyl,pyrrolyl, isopyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl,isoimidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl,pyrazolidinyl, triazolyl, tetrazolyl, dithiolyl, oxathiolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl,thiazolidinyl, isothiazolidinyl, thiodiazolyl, oxathiazolyl, oxadiazolyl(including 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl (also known as“azoximyl”), 1,2,5-oxadiazolyl (also known as “furazanyl”), or1,3,4-oxadiazolyl), oxatriazolyl (including 1,2,3,4-oxatriazolyl or1,2,3,5-oxatriazolyl), dioxazolyl (including 1,2,3-dioxazolyl,1,2,4-dioxazolyl, 1,3,2-dioxazolyl, or 1,3,4-dioxazolyl), oxathiazolyl,oxathiolyl, oxathiolanyl, pyranyl (including 1,2-pyranyl or1,4-pyranyl), dihydropyranyl, pyridinyl (also known as “azinyl”),piperidinyl, diazinyl (including pyridazinyl (also known as“1,2-diazinyl”), pyrimidinyl (also known as “1,3-diazinyl” or“pyrimidyl”), or pyrazinyl (also known as “1,4-diazinyl”)), piperazinyl,triazinyl (including s-triazinyl (also known as “1,3,5-triazinyl”),as-triazinyl (also known 1,2,4-triazinyl), and v-triazinyl (also knownas “1,2,3-triazinyl”)), oxazinyl (including 1,2,3-oxazinyl,1,3,2-oxazinyl, 1,3,6-oxazinyl (also known as “pentoxazolyl”),1,2,6-oxazinyl, or 1,4-oxazinyl), isoxazinyl (including o-isoxazinyl orp-isoxazinyl), oxazolidinyl, isoxazolidinyl, oxathiazinyl (including1,2,5-oxathiazinyl or 1,2,6-oxathiazinyl), oxadiazinyl (including1,4,2-oxadiazinyl or 1,3,5,2-oxadiazinyl), morpholinyl, azepinyl,oxepinyl, thiepinyl, and diazepinyl.

A heterocyclyl alternatively may be 2 or 3 rings fused together, whereinat least one such ring contains a heteroatom as a ring atom (i.e.,nitrogen, oxygen, or sulfur). Such substituents include, for example,indolizinyl, pyrindinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl,naphthyridinyl, pyridopyridinyl (including pyrido[3,4-b]-pyridinyl,pyrido[3,2-b]-pyridinyl, or pyrido[4,3-b]-pyridinyl), and pteridinyl.Other examples of fused-ring heterocyclyls include benzo-fusedheterocyclyls, such as indolyl, isoindolyl (also known as“isobenzazolyl” or “pseudoisoindolyl”), indoleninyl (also known as“pseudoindolyl”), isoindazolyl (also known as “benzpyrazolyl”),benzazinyl (including quinolinyl (also known as “1-benzazinyl”) orisoquinolinyl (also known as “2-benzazinyl”)), phthalazinyl,quinoxalinyl, quinazolinyl, benzodiazinyl (including cinnolinyl (alsoknown as “1,2-benzodiazinyl”) or quinazolinyl (also known as“1,3-benzodiazinyl”)), benzopyranyl (including “chromanyl” or“isochromanyl”), benzothiopyranyl (also known as “thiochromanyl”),benzoxazolyl, indoxazinyl (also known as “benzisoxazolyl”), anthranilyl,benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl (also knownas “coumaronyl”), isobenzofuranyl, benzothienyl (also known as“benzothiophenyl”, “thionaphthenyl”, or “benzothiofuranyl”),isobenzothienyl (also known as “isobenzothiophenyl”,“isothionaphthenyl”, or “isobenzothiofuranyl”), benzothiazolyl,benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl(including 1,3,2-benzoxazinyl, 1,4,2-benzoxazinyl, 2,3,1-benzoxazinyl,or 3,1,4-benzoxazinyl), benzisoxazinyl (including 1,2-benzisoxazinyl or1,4-benzisoxazinyl), tetrahydroisoquinolinyl, carbazolyl, xanthenyl, andacridinyl.

The term “2-fused′ring” heterocyclyl (alone or in combination withanother term(s)) means a saturated, partially saturated, or arylheterocyclyl containing 2 fused rings. Examples of 2-fused-ringheterocyclyls include indolizinyl, pyrindinyl, pyranopyrrolyl,4H-quinolizinyl, purinyl, naphthyridinyl, pyridopyridinyl, pteridinyl,indolyl, isoindolyl, indoleninyl, isoindazolyl, benzazinyl,phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl, benzopyranyl,benzothiopyranyl, benzoxazolyl, indoxazinyl, anthranilyl, benzodioxolyl,benzodioxanyl, benzoxadiazolyl, benzofuranyl, isobenzofuranyl,benzothienyl, isobenzothienyl, benzothiazolyl, benzothiadiazolyl,benzimidazolyl, benzotriazolyl, benzoxazinyl, benzisoxazinyl, andtetrahydroisoquinolinyl.

The term “heteroaryl” (alone or in combination with another term(s))means an aromatic heterocyclyl containing from 5 to 14 ring atoms. Aheteroaryl may be a single ring or 2 or 3 fused rings. Examples ofheteroaryl substituents include 6-membered ring substituents such aspyridyl, pyrazyl, pyrimidinyl, and pyridazinyl; 5-membered ringsubstituents such as 1,3,5-, 1,2,4- or 1,2,3-tiiazinyl, imidazyl,furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-,1,2,4-, 1,2,5-, or 1,3,4-oxadiazolyl and isothiazolyl; 6/5-memberedfused ring substituents such as benzothiofuranyl, isobenzothiofuranyl,benzisoxazolyl, benzoxazolyl, purinyl, and anthranilyl; and 6/6-memberedfused rings such as 1,2-, 1,4-, 2,3- and 2,1-benzopyronyl, quinolinyl,isoquinolinyl, cinnolinyl, quinazolinyl, and 1,4-benzoxazinyl.

The term “heterocyclylalkyl” (alone or in combination with anotherterm(s)) means alkyl substituted with a heterocyclyl.

The term “heterocycloalkyl” (alone or in combination with anotherterm(s)) means a fully saturated heterocyclyl.

In some preferred embodiments, a carbocyclyl or heterocyclyl optionallyis substituted with one or more substituents independently selected fromthe group consisting of halogen, hydroxy (—OH), cyano (—CN), nitro(—NO₂), thiol (—SH), carboxy (—C(O)—OH), amino (—NH₂), keto (═O),aminocarbonyl, alkyl, aminoalkyl, carboxyalkyl, alkylamino,alkylaminoalkyl, aminoalkylamino, alkylaminocarbonyl,aminocarbonylalkyl, alkoxycarbonylalkyl, alkenyl, alkynyl,alkylthioalkyl, alkylsulfinyl, alkylsulfinylalkyl, alkylsulfonyl,alkylsulfonylalkyl, alkylthio, carboxyalkylthio, alkylcarbonyl (alsoknown as “alkanoyl”), alkylcarbonyloxy, alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkoxy, alkoxyalkylthio,alkoxycarbonylalkylthio, carboxyalkoxy, alkoxycarbonylalkoxy,carbocyclyl, carbocyclylaminocarbonyl, carbocyclylaminoalkyl,carbocyclylalkoxy, carbocyclyloxyalkyl, carbocyclylalkoxyalkyl,carbocyclylthioalkyl, carbocyclylsulfinylalkyl,carbocyclylsulfonylalkyl, carbocyclylalkyl, carbocyclyloxy,carbocyclylthio, carbocyclylalkylthio, carbocyclylamino,carbocyclylalkylamino, carbocyclylcarbonylamino, carbocyclylcarbonyl,carbocyclylalkyl, carbocyclylcarbonyloxy, carbocyclyloxycarbonyl,carbocyclylalkoxycarbonyl, carbocyclyloxyalkoxycarbocyclyl,carbocyclylthioalkylthiocarbocyclyl, carbocyclylthioalkoxycarbocyclyl,carbocyclyloxyalkylthiocarbocyclyl, heterocyclyl,heterocyclylaminocarbonyl, heterocyclylaminoalkyl, heterocyclylalkoxy,heterocyclyloxyalkyl, heterocyclylalkoxyalkyl, heterocyclylthioalkyl,heterocyclylsulfinylalkyl, heterocyclylsulfonylalkyl, heterocyclylalkyl,heterocyclyloxy, heterocyclylthio, heterocyclylalkylthio,heterocyclylamino, heterocyclylalkylamino, heterocyclylcarbonylamino,heterocyclylcarbonyl, heterocyclylalkylcarbonyl,heterocyclyloxycarbonyl, heterocyclylcarbonyloxy,heterocyclylalkoxycarbonyl, heterocyclyloxyalkoxyheterocyclyl,heterocyclylthioalkylthioheterocyclyl,heterocyclylthioalkoxyheterocyclyl, andheterocyclyloxyalkylthioheterocyclyl.

In some preferred embodiments, a carbocyclyl or heterocyclyl optionallyis substituted with one or more substituents independently selected fromthe group consisting of halogen, hydroxy, cyano, nitro, thiol, carboxy,amino, aminocarbonyl, C₁-C₆-alkyl, amino-C₁-C₆-alkyl, keto,carboxy-C₁-C₆-alkyl, C₁-C₆-alkylamino, C₁-C₆-alkylamino-C₁-C₆-alkyl,amino-C₁-C₆-alkylamino, C₁-C₆-alkylaminocarbonyl,aminocarbonyl-C₁-C₆-alkyl, C₁-C₆-alkoxycarbonyl-C₁-C₆-alkyl,C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₆-alkylthio-C₁-C₆-alkyl,C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfinyl-C₁-C₆-alkyl,C₁-C₆-alkylsulfonyl, C₁-C₆-alkylsulfonyl-C₁-C₆-alkyl, C₁-C₆-alkylthio,carboxy-C₁-C₆-alkylthio, C₁-C₆-alkylcarbonyl, C₁-C₆-alkylcarbonyloxy,C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxycarbonyl,C₁-C₆-alkoxycarbonyl-C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₆-alkylthio,C₁-C₆-alkoxycarbonyl-C₁-C₆-alkylthio, carboxy-C₁-C₆-alkoxy,C₁-C₆-alkoxycarbonyl-C₁-C₆-alkoxy, aryl, arylaminocarbonyl,arylamino-C₁-C₆-alkyl, aryl-C₁-C₆-alkoxy, aryloxy-C₁-C₆-alkyl,aryl-C₁-C₆-alkoxy-C₁-C₆-alkyl, arylthio-C₁-C₆-alkyl,arylsulfinyl-C₁-C₆-alkyl, arylsulfonyl-C₁-C₆-alkyl, aryl-C₁-C₆-alkyl,aryloxy, arylthio, aryl-C₁-C₆-alkylthio, arylamino,aryl-C₁-C₆-alkylamino, arylcarbonylamino, arylcarbonyl,aryl-C₁-C₆-alkylcarbonyl, arylcarbonyloxy, aryloxycarbonyl,aryl-C₁-C₆-alkoxycarbonyl, aryloxy-C₁-C₆-alkoxyaryl,arylthio-C₁-C₆-alkylthioaryl, arylthio-C₁-C₆-alkoxyaryl,aryloxy-C₁-C₆-alkylthioaryl, cycloalkyl, cycloalkyl aminocarbonyl,cycloalkyl amino-C₁-C₆-alkyl, cycloalkyl -C₁-C₆-alkoxy, cycloalkyloxy-C₁-C₆-alkyl, cycloalkyl-C₁-C₆-alkoxy-C₁-C₆-alkyl, cycloalkylthio-C₁-C₆-alkyl, cycloalkyl sulfinyl-C₁-C₆-alkyl, cycloalkylsulfonyl-C₁-C₆-alkyl, cycloalkyl-C₁-C₆-alkyl, cycloalkyloxy,cycloalkylthio, cycloalkyl-C₁-C₆-alkylthio, cycloalkylamino,cycloalkyl-C₁-C₆-alkylamino, cycloalkylcarbonylamino,cycloalkylcarbonyl, cycloalkyl-C₁-C₆-alkylcarbonyl,cycloalkylcarbonyloxy, cycloalkyloxycarbonyl,cycloalkyl-C₁-C₆-alkoxycarbonyl, heteroaryl, heteroarylaminocarbonyl,heteroarylamino-C₁-C₆-alkyl, heteroaryl-C₁-C₆-alkoxy,heteroaryloxy-C₁-C₆-alkyl, heteroaryl-C₁-C₆-alkoxy-C₁-C₆-alkyl,heteroarylthio-C₁-C₆-alkyl, heteroarylsulfinyl-C₁-C₆-alkyl,heteroarylsulfonyl-C₁-C₆-alkyl, heteroaryl-C₁-C₆-alkyl, heteroaryloxy,heteroarylthio, heteroaryl-C₁-C₆-alkylthio, heteroarylamino,heteroaryl-C₁-C₆-alkylamino, heteroarylcarbonylamino,heteroarylcarbonyl, heteroaryl-C₁-C₆-alkylcarbonyl,heteroaryloxycarbonyl, heteroarylcarbonyloxy, andheteroaryl-C₁-C₆-alkoxycarbonyl. Here, any substitutable carbonoptionally is substituted with one or more halogen. In addition, thecycloalkyl, aryl, and heteroaryl typically have 3 to 6 ring atoms, andmore typically 5 or 6 ring atoms.

In some preferred embodiments, a carbocyclyl or heterocyclyl optionallyis substituted with one or more substituents independently selected fromthe group consisting of halogen, hydroxy, carboxy, keto, alkyl, alkoxy,alkoxyalkyl, alkylcarbonyl (also known as “alkanoyl”), aryl, arylalkyl,arylalkoxy, arylalkoxyalkyl, arylalkoxycarbonyl, cycloalkyl,cycloalkylalkyl, cycloalkylalkoxy, cycloalkylalkoxyalkyl, andcycloalkylalkoxycarbonyl.

In some preferred embodiments, a carbocyclyl or heterocyclyl optionallyis substituted with one or more substituents independently selected fromthe group consisting of halogen, hydroxy, carboxy, keto, C₁-C₆-alkyl,C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-alkylcarbonyl, aryl,aryl-C₁-C₆-alkyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkoxy-C₁-C₆-alkyl,aryl-C₁-C₆-alkoxycarbonyl, cycloalkyl, cycloalkyl-C₁-C₆-alkyl,cycloalkyl-C₁-C₆-alkoxy, cycloalkyl-C₁-C₆-alkoxy-C₁-C₆-alkyl, andcycloalkyl-C₁-C₆-alkoxycarbonyl. The alkyl, alkoxy, alkoxyalkyl,alkylcarbonyl, aryl, arylalkyl, arylalkoxy, arylalkoxyalkyl, orarylalkoxycarbonyl substituent(s) may further be substituted with one ormore halogen. The aryls or cycloalkyls typically have from 3 to 6 ringatoms, and more typically from 5 to 6 ring atoms.

In some preferred embodiments, a carbocyclyl or heterocyclyl optionallyis substituted with up to three substituents independently selected fromthe group consisting of halogen, hydroxy, alkyl, alkoxy, amino,alkylthio, keto, and alkylamino.

In some preferred embodiments, a carbocyclyl or heterocyclyl optionallyis substituted with up to three substituents independently selected fromthe group consisting of halogen, hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy,amino, C₁-C₆-alkylthio, keto, and C₁-C₆-alkylamino.

In some preferred embodiments, a carbocyclyl or heterocyclyl optionallyis substituted with up to three substituents independently selected fromthe group consisting of halogen, nitro, alkyl, haloalkyl, alkoxy,haloalkoxy, and amino.

In some preferred embodiments, a carbocyclyl or heterocyclyl optionallyis substituted with up to three substituents independently selected fromthe group consisting of halogen, nitro, C₁-C₆-alkyl, halo-C₁-C₆-alkyl,C₁-C₆-alkoxy, halo-C₁-C₆-alkoxy, and amino.

In some preferred embodiments, a carbocyclyl or heterocyclyl optionallyis substituted with up to three substituents independently selected fromthe group consisting of halogen, alkyl, haloalkyl, alkoxy, andhaloalkoxy.

In some preferred embodiments, a carbocyclyl or heterocyclyl optionallyis substituted with up to three substituents independently selected fromthe group consisting of halogen, C₁-C₆-alkyl, halo-C₁-C₆-alkyl,C₁-C₆-alkoxy, and halo-C₁-C₆-alkoxy.

A substituent is “substitutable” if it comprises at least one carbon ornitrogen atom that is bonded to one or more hydrogen atoms. Thus, forexample, hydrogen, halogen, and cyano do not fall within thisdefinition.

If a substituent is described as being “substituted”, a non-hydrogenradical is in the place of a hydrogen radical on a carbon or nitrogen ofthe substituent. Thus, for example, a substituted alkyl substituent isan alkyl substituent wherein at least one non-hydrogen radical is in theplace of a hydrogen radical on the alkyl substituent. To illustrate,monofluoroalkyl is alkyl substituted with a fluoro radical, anddifluoroalkyl is alkyl substituted with two fluoro radicals. It shouldbe recognized that if there are more than one substitutions on asubstituent, each non-hydrogen radical may be identical or different(unless otherwise stated).

If a substituent is described as being “optionally substituted”, thesubstituent may be either (1) not substituted or (2) substituted. If asubstituent is described as being optionally substituted with up to aparticular number of non-hydrogen radicals, that substituent may beeither (1) not substituted; or (2) substituted by up to that particularnumber of non-hydrogen radicals or by up to the maximum number ofsubstitutable positions on the substituent, whichever is less. Thus, forexample, if a substituent is described as a heteroaryl optionallysubstituted with up to 3 non-hydrogen radicals, then any heteroaryl withless than 3 substitutable positions would be optionally substituted byup to only as many non-hydrogen radicals as the heteroaryl hassubstitutable positions. To illustrate, tetrazolyl (which has only onesubstitutable position) would be optionally substituted with up to onenon-hydrogen radical. To illustrate further, if an amino nitrogen isdescribed as being optionally substituted with up to 2 non-hydrogenradicals, then a primary amino nitrogen will be optionally substitutedwith up to 2 non-hydrogen radicals, whereas a secondary amino nitrogenwill be optionally substituted with up to only 1 non-hydrogen radical.

The terms “substituent” and “radical” are interchangeable.

A prefix attached to a multi-component substituent only applies to thefirst component. To illustrate, the term “alkylcycloalkyl” contains twocomponents: alkyl and cycloalkyl. Thus, the C₁-C₆-prefix onC₁-C₆-alkylcycloalkyl means that the alkyl component of thealkylcycloalkyl contains from 1 to 6 carbon atoms; the C₁-C₆-prefix doesnot describe the cycloalkyl component. To illustrate further, the prefix“halo” on haloalkoxyalkyl indicates that only the alkoxy component ofthe alkoxyalkyl substituent is substituted with one or more halogenradicals. If halogen substitution may alternatively or additionallyoccur on the alkyl component, the substituent would instead be describedas “halogen-substituted alkoxyalkyl” rather than “haloalkoxyalkyl.” Andfinally, if the halogen substitution may only occur on the alkylcomponent, the substituent would instead be described as“alkoxyhaloalkyl.”

If substituents are described as being “independently selected” from agroup, each substituent is selected independent of the other. Eachsubstituent therefore may be identical to or different from the othersubstituent(s).

The term “pharmaceutically-acceptable” is used adjectivally in thisspecification to mean that the modified noun is appropriate for use as apharmaceutical product or as a part of a pharmaceutical product.

With reference to the use of the words “comprise” or “comprises” or“comprising” in this patent (including the claims), Applicants note thatunless the context requires otherwise, those words are used on the basisand clear understanding that they are to be interpreted inclusively,rather than exclusively, and that Applicants intend each of those wordsto be so interpreted in construing this patent, including the claimsbelow.

The following are definitions for various abbreviations:

-   -   “boc” is tert-butoxycarbonyl.    -   “CBC” is 4-chlorobenzoyl chloride.    -   “DBU” is 1,8-diazabicyclo[5.4.0]undec-7-ene.    -   “DMAP” is dimethylaminopyridine.    -   “DMF” is dimethylformamide.    -   “DMSO” is dimethylsulfoxide.    -   “DSC” is differential scanning calorimetry.    -   “equiv.” is equivalent.    -   “h” or “hr” is hour or hours.    -   “HCl” is hydrochloric acid.    -   “IPA” is isopropyl alcohol.    -   “KF” is coulometric water determination according to the Karl        Fisher method.    -   “LDA” is lithium diisopropylamide.    -   “LiHMDS” is lithium hexamethyldisilazide.    -   “mCPBA” is 3-chloroperbenzoic acid.    -   “min” is minute or minutes.    -   “MW” is molecular weight.    -   “NaH” is sodium hydride.    -   “NaOH” is sodium hydroxide.    -   “NMP” is 1-methyl-2-pyrrolidinone (also called, for example,        “N-methylpyrrolidinone”, “1-methyl-2-pyrrolidone”,        “N-methylpyrrolidone”, “N-methyl-2-pyrrolidinone”,        “methylpyrrolidinone”, and “N-methyl-α-pyrrolidone”).    -   “N₂” is nitrogen gas.    -   “ROI” is residue on ignition.    -   “tBuOK” is potassium tert-butoxide.    -   “TFA” is trifluoroacetic acid.    -   “THF” is tetrahydrofuran.    -   “Ethanol 3A” is 95% absolute ethanol and 5% methanol (HPLC        grade).

EXAMPLES

The following examples are merely illustrative, and not limiting to theremainder of this disclosure in any way. These examples are directed tothe preparation of a particularly preferred compound(N-(2-hydroxyacetyl)-5-(4-piperidyl)-4-(4-pyrimidinyl)-3-(4-chlorophenyl)pyrazole)and a salt. One skilled in the art, however, can prepare other compounds(and salts thereof) falling within the scope of Formula I above byapplying the general principles illustrated in this example and otherportions of the this specification alone or in combination with existingknowledge in the art. Existing knowledge in the art includes, forexample, PCT Publication No. WO 00/31063 (incorporated herein byreference).

Example 1 Preparation ofN-(2-hydroxyacetyl)-5-(4-piperidyl)-4-(4-pyrimidinyl)-3-(4-chlorophenyl)pyrazole

Part A. Preparation of ethyl N-(t-butoxycarbonyl)isonipecotate (3):

This reaction was conducted in a jacketed, 49 L reactor equipped with aretreat curve agitator, nitrogen purge system, and condenser system. Thereactor was charged with di-t-butyl dicarbonate (1) in tetrahydrofuran(“THF”) (75%, 4.674 Kg, 16.06 mol) and tetrahydrofuran (5.50 Kg, 76.3moles). After cooling the mixture to 0° C., ethyl isonipecotate (2)(2.500 Kg, 15.90 mol) was charged to the reactor while maintaining thecontents at a temperature of from 0 to 15° C. After all the ethylisonipecotate was added, the contents were warmed to 25° C., and thenstirred for 2 hours at that temperature. The mixture was then cooled to0° C. The THF was then removed by vacuum distillation until the batchtemperature reached 80° C. Afterward, the contents were cooled to 25° C.This yielded 3.99 Kg of product in the form of an amber oil. Theconcentration of the Boc-protected ethyl isonipecotate (3) was 96.3% (byweight).

TABLE 1 Reaction Summary for Part A wt density volume MW equiv. (kg)moles (g/mL) (L) materials compound (1) 218.25 1.01 4.674 16.06 0.9135.12 (75%) tetrahydrofuran 72.11 4.8 5.50 76.3 0.889 6.19 compound (2)157.21 1.00 2.500 15.90 1.020 2.45 product compound (3) 257.33 (1.00)(4.092) (15.90) The numbers in parenthesis in the above table aretheoretical..

Part B. Preparation of theN-(t-butoxycarbonyl)-1-(4-piperidyl)-2-(4-pyrimidyl)-1-ethanone (5):

This reaction was conducted in the same jacketed, 49 L reactor equippedwith retreat curve agitator, nitrogen purge system, bottom valve forremoval of a lower portion of the contents, and Dean-Stark trap andcondenser system. The reactor was first purged with nitrogen. Afterward,20% potassium t-butoxide in THF (21.06 Kg, 37.54 mol) was charged to thereactor under N₂ using a cannula system. This solution was then cooledto 0° C., and the reactor was next charged with 4-methylpyrimidine (4)(1.53 Kg, 16.27 mol) while maintaining the temperature of the reactorcontents at from 0 to 5° C. Immediately afterward, the Boc-protectedethyl isonipecotate (3) prepared as shown in Part A (3.99 Kg, 15.51 mol)was charged neat over 30 minutes while continuing to maintain thereactor contents at a temperature of from 0 to 5° C. Afterward, thereactor contents were stirred for 3 hours while being maintained at 5°C. The temperature of the reactor contents was then increased to 10° C.,and then maintained at that temperature for 1 hour. Subsequently, 33%aqueous acetic acid solution (6.71 Kg, 36.88 mol) was charged to thereaction mixture while maintaining the reaction mixture at below 30° C.After stirring the resulting mixture for 30 minutes, it was allowed tostand for 30 minutes. The aqueous layer was then separated. Afterward,ammonium chloride solution (2.96 Kg, 3.87 mol) was charged to thereactor. The resulting mixture was stirred for 30 minutes. Afterallowing the mixture to stand for 30 minutes, the aqueous layer wasseparated. The THF was removed from the organic remaining layer byslowly raising the batch temperature under vacuum (200 torr) until thetemperature reached 60-65° C. using a distillation apparatus. The finalconcentrate was in the form of an amber oil. This oil and toluene (12.22Kg, 132.6 mol) were combined in the reactor, and the resulting mixturewas stirred at room temperature for 15 minutes. Afterward, water (4.01kg, 222.5 mol) was added to the reactor, and stirring was continued foran additional 30 minutes at room temperature. The reactor contents wereallowed to stand for 60 minutes. The aqueous layer was then separated.

The top layer (i.e., the organic layer) was then used as is to preparethe hydrazone in Part C.

TABLE 2 Reaction Summary for Part B wt density volume materials MWequiv. (kg) moles (g/mL) (L) potassium 112.2 2.42 21.06 37.54 0.902 23.3t-butoxide in THF (20%) compound (3) 257.3 1.00 3.99 15.51 1.034 3.86compound (4) 94.11 1.05 1.53 16.27 1.031 1.48 33% acetic acid 60.05 2.406.71 36.88 1.049 6.4 solution 7% ammonium 53.49 0.25 2.96 3.87 chloridesolu- tion toluene 92.14 10.20 12.22 132.6 0.865 14.1 water 18.02 14.354.01 222.5 1.000 4.01

Part C. Preparation of theN-(t-butoxycarbonyl)-1-(4-piperidyl)-2-(4-pyrimidyl)-1-ethanonep-toluenesulfonyl hydrazone (7):

Toluenesulfonylhydrazide (6) (2.6 Kg, 13.96 mol) was combined with thereaction mixture from Part B in the same reactor. The resulting mixturewas heated to 70° C. while being stirred and maintained at thistemperature for 2 hours. The reaction mixture was then refluxed at 70°C. under reduced pressure (200 torr) using the Dean-Stark moisture trapfor 1 hour. Afterward, the mixture was cooled to 0° C. over 1.5 hours,and then maintained at 0° C. for at least 12 hours. The resulting solidswere collected using a filter (using a 4 micron filter cloth). The wetcake was then washed with toluene (3.79 Kg, 41.13 mol, 0 to 5° C.),followed by ethyl acetate (3.95 Kg, 44.83 mol, 0 to 5° C.). After thecake was dried on the filter for 2 hours, and then transferred to avacuum oven at 40° C. for at least 4 hour. This yielded 5.15 Kg (70%) ofa light yellow solid. The concentration of hydrazone (7) was 99.2% (byweight).

TABLE 3 Reaction Summary for Part C wt density volume MW equiv. (kg)moles (g/mL) (L) materials compound (6) 186.2 0.90 2.60 13.96 toluene92.14 2.65 3.79 41.13 0.865 4.38 ethyl acetate 88.10 2.89 3.95 44.830.902 4.38 product compound (7) 473.60 (1.00) (7.34) (15.51) The numbersin parenthesis in the above table are theoretical.

Part D. Preparation of tert-butyl4-{5-(4-chlorophenyl)-1-[(4-methylphenyl)sulfonyl]-4-pyrimidin-4-yl-1H-pyrazol-3-yl}piperidine-1-carboxylate(9):

This reaction was conducted in the same jacketed, 49 L reactor equippedwith a retreat curve agitator, metering pump, nitrogen purge system, andcondenser system. The reactor was first purged with nitrogen at roomtemperature. The clean, dry reactor was then charged with the hydrazone(7) prepared as shown in Part C (2.77 Kg, 5.85 mol),dimethylaminopyridine (“DMAP”) (0.0715 Kg, 0.585 mol), tetrahydrofuran(12.47 Kg, 173.04 mol), and triethylamine (0.829 Kg, 8.19 mol). Next,4-chlorobenzoyl chloride (8) (“CBC”) (1.28 Kg, 7.31 moles) was added tothe reactor over 20 minutes using a pump at such a rate as to keep theinternal temperature less than 40° C. The contents turned deep yellowand formed a precipitate. After the addition of the 4-chlorobenzoylchloride, the reaction mixture was heated to 65° C. over 30 minutes, andthen maintained at that temperature for 5 hours. Subsequently, thetemperature of the mixture was decreased to room temperature, and water(2.77 kg, 153.7 mol) was added. The resulting mixture was stirred for0.5 hours. Subsequently, the organic and aqueous phases were allowed toseparate, and the aqueous phase was removed from the bottom of thereactor. To the remaining organic layer was added 22% aqueous ammoniumchloride solution (4.62 L). The resulting mixture was stirred for 0.5hours. The stirring was stopped and the organic and aqueous phases wereallowed to separate. The aqueous phase was removed from the bottom ofthe reactor. An IPA-water mixture (1:1 (vol:vol); 22.16 L) was thenadded to the remaining organics over 2 hours. Subsequently, theresulting mixture was stirred for 5 hours. The solids were filtered (4micron filter cloth), washed with IPA-water (1:1 (vol:vol); 7.39 L), anddried on the filter for 2 hours. The wet cake was transferred to avacuum oven at 80° C. (house vacuum) for 6 hours. This yielded 2.85 Kg(84.6%) of solids. The concentration of the protected pyrazoleintermediate (9) was 99.0% (by weight).

TABLE 4 Reaction Summary for Part D wt density volume MW equiv. (kg)moles (g/mL) (L) material compound (7) 473.59 1.0 2.77 5.85tetrahydrofuran 72.11 29.58 12.47 173.04 0.889 14.0 (THF) compound (8)175.01 1.25 1.28 7.31 1.377 0.93 triethylamine 101.19 1.43 0.829 8.190.726 1.14 (TEA) 4-dimethyl- 122.17 0.102 0.0715 0.585 amino pyridine(DMAP) water 18 26.3 2.77 153.7 1.000 2.77 22% NH₄Cl 53.49 3.5 18.474.62 IPA-water 22.16 anti-solvent IPA-water 7.39 cake wash productcompound (9) 594.13 (1.0) (3.48) (5.85) The numbers in parenthesis inthe above table are theoretical.

Part E. Preparation of5-(4-piperidyl)-4-(4-pyrimidinyl)-3-(4-chlorophenyl)pyrazole (10):

The following discussion describes two variations of this reaction:

A. First Variation

In the first variation, the above reaction was conducted in the samejacketed, 49 L reactor equipped with a retreat curve agitator, nitrogenpurge, and metering pump. The reactor was charged with the protectedpyrazole intermediate (9) prepared as shown in Part D (5.0 Kg, 8.42 mol)and toluene (10.0 kg, 108.5 mol). After initiating stirring, 37% HCl(6.64 Kg, 67.4 mol) was added over 15 minutes via a pump. Immediate gasevolution and a temperature increase from 22.2° C. to 28.4° C. wereobserved. Two phases appeared within 10 minutes. The temperature wasmaintained at 20° C. for 1.0 hour. Afterward, water (20 Kg, 1110 mol)was added, and the resulting mixture was stirred for 20 minutes. Theorganic and aqueous phases were then separated, and the aqueous phasewas introduced back into the reactor. The reactor was then additionallycharged with 6 N NAOH (10.0 Kg, 60.2 mol) via a pump over 30 minutes.This increased the pH to 12, and caused a white/off-white slurry toform. The mixture was heated to 75° C. over 30 minutes, and then held atthat temperature for an additional 2 hours. Subsequently, the mixturewas cooled to 25° C. The so lids were filtered with a 4 micron filtercloth, washed with deionized water (3×15 Kg), and air-dried for 45minutes, i.e., until a constant weight (LOD<50%) was observed. Theresulting cake was introduced into the reactor, along with acetonitrile(15 Kg). This mixture was heated to reflux, and then maintained atreflux for 1 hour. Subsequently, the mixture was cooled to 5° C., andthen maintained at that temperature for 30 minutes. The solids werefiltered with a 4 micron filter cloth, washed with acetonitrile (15 Kg),and dried in a vacuum oven at 85° C. for 12 hours (LOD<1%). This yielded2.64 Kg (92%) of slightly off-white solids. The concentration of5-(4-piperidyl)-4-(4-pyrimidinyl)-3-(4-chlorophenyl)pyrazole was greaterthan 97% (by weight). No single impurity was present at >1% (by weight).The residue on ignition (“ROI”) was <1%, and the coulometric waterdetermination according to the Karl Fisher method (“KF”) also was <1%.

TABLE 5 Reaction Summary for Part E (First Variation) equiv. vs. wtratio to compound compound density volume MW (9) wt (Kg) (9) moles(g/mL) (L) material compound (9) 594.13 1.0 5.0 1 8.42 — — 37% HCl 36.468.0 6.64 @ 37% 1.3 67.4 1.200 5.53 toluene 92.14 12.9 10.0 2 108.5 0.86511.6 6 N NaOH 40.0 7.2 10.0 @ 6N 2 60.2 1.22 8.2 water addition 18.02132 20.0 4 1,110 1.000 20.0 water wash 18.02 99 15.0 3 832 1.000 15.0 #1water wash 18.02 99 15.0 3 832 1.000 15.0 #2 water wash 18.02 99 15.0 3832 1.000 15.0 #3 acetonitrile 41.05 43 15.0 3 365 0.786 19.0trituration acetonitrile 41.05 43 15.0 3 365 0.786 19.0 wash productcompound (10) 339.83 (1.0) (2.86) (8.42) The numbers in parenthesis inthe above table are theoretical.

B. Second Variation

In the second variation, the above reaction was likewise conducted inthe same jacketed, 49 L reactor equipped with a retreat curve agitator,nitrogen purge, and metering pump. The reactor was charged with theprotected pyrazole intermediate (9) prepared as shown in Part D (5.0 Kg,8.42 mol) and toluene (10.0 kg, 108.5 mol). After initiating stirring,37% HCl (6.64 Kg, 67.4 mol) over 16 minutes. A temperature increase from20 to 28° C. was observed during the addition. The temperature of themixture was then increased to 70° C. over a 30 minutes period (1.5°C./minute), and held at 70° C. for 2 hours. The mixture was then cooledto 23° C. over 1 hour. After adding water (20 L), the mixture wasstirred for 30 minutes. Agitation was then halted, and the phases wereallowed to separate for 57 min. The bottom phase (i.e., the aqueousphase, which contained product) was removed from the reactor. Afterremoving the top phase (i.e., the organic phase), the reactor was rinsedwith toluene, followed by water, to remove residuals. The aqueous phasecontaining the product was then transferred back to the reactor. Thereactor was then additionally charged with 6 N NaOH (10.0 kg, 54.74 mol,6.5 equiv.) over 27 minutes. The observed final pH was 12.25. Thereaction mixture was then heated to 75° C. over 30 minutes and held atthat temperature for 2 hours. The slurry was then quickly cooled to 25°C. The product (in the form of solids) was collected by filtration usinga pressure filter, and washed on the filter with water (2×15 L). Thefinal pH of the rinse was 7.5. The cake was pulled dry for 60 minutes.This provided wet cake with a 19.4% LOD. The wet cake was charged backto the reactor, along with acetonitrile (15.0 kg, 19.1 L). The resultingmixture was heated to reflux (82° C.), and held at that temperature for2 hours and 29 minutes. The slurry was then cooled to 5° C., and thenheld at that temperature for 30 minutes. The resulting product wasfiltered and then filter pulled dry until no mother languor was comingoff the filter. The cake was rinsed with acetonitrile (18 L) and thenpulled dry for 2 hours. The wet cake (LOD 12.2%) was transferred to avacuum dryer at 85° C. for 16 hours and 20 minutes (although it isbelieved that a time period of from 6 to 12 hours would have beensufficient). This provided 2.64 Kg at 92.2% isolated yield.

Part F. Preparation of the NMP solvate ofN-(2-hydroxyacetyl)-5-(4-piperidyl)-4-(4-pyrimidinyl)-3-(4-chlorophenyl)pyrazole(12):

The following discussion describes three variations of this reaction:

A. First Variation

This reaction was conducted in a jacketed, 0.1 L reactor equipped withan agitator, nitrogen purge, thermocouple, and condenser. The reactorwas charged with5-(4-piperidyl)-4-(4-pyrimidinyl)-3-(4-chlorophenyl)pyrazole (10)prepared as shown in Part E (10 g, 0.029 mol); 1-methyl-2-pyrrolidinone(20 g, 0.20 mol); butyl glycolate (11) (9.7 g, 0.073 mol), and1,8-diazabicyclo[5.4.0]undec-7-ene (“DBU”) (0.45 g, 0.0029 mol). Afterstirring was initiated, the mixture was heated to about 110° C., andthen maintained at that temperature for 3 hours. At that point, it wasdetermined by HPLC that conversion from starting material to product hadceased (i.e., <3 area % starting material remained). The reactorcontents were then cooled to 25° C. over 1 hour. Ethanol 3A (1.74 g,0.038 mol) was then charged to the reactor. The resulting mixture wasmaintained at 25° C. for an additional hour, and then further cooled to0° C. over 30 minutes. This temperature was maintained for an additional2 hours. The solids were collected via filtration using a 4 micronfilter cloth, washed with NMP (2×18 g), and air-dried on the filtergiving rise to the NMP solvate of the desired product, which wasanalyzed via differential scanning calorimetry (“DSC”). The solids wereintroduced to the reactor along with 100 mL of ethanol. The resultingmixture was then heated to reflux, and maintain at reflux for 4 hours.Afterward, the mixture was cooled to 15° C. over 3 hours. The productwas then isolated by filtration using a 4 micron filter cloth, washed(using a displacement wash) with ethanol 3A (2×33 g), and air-dried onthe filter. This yielded 9.0 g of white/off-white/yellow crystals (78%yield) (HPLC weight % >98%).

TABLE 6 Reaction Summary for Part F wt. density volume MW equiv. (g)moles (g/mL) (mL) materials compound (10) 339.83 1.00 10.0 0.0291-methyl-2- 99.13 6.96 20.0 0.20 1.028 15.6 pyrrolidinone 1,8-Diaza-152.24 0.10 0.45 0.0029 1.018 0.44 bicyclo-(5.4.0) undec-7-ene compound(11) 132.16 2.5 9.7 0.073 1.019 9.5 Ethanol 3A 46.01 1.31 1.7 0.0380.790 2.2 1-methly-2- 99.13 6.26 18.0 0.18 1.028 17.5 pyrrolidinone(wash) 1-methly-2- 99.13 6.26 18.0 0.18 1.028 17.5 pyrrolidinone (wash)Ethanol 3A 46.01 59.2 79 1.72 0.790 100 Ethanol 3A 46.01 24.7 33 0.720.790 26.1 (wash) Ethanol 3A 46.01 24.7 33 0.72 0.790 26.1 (wash) wtdensity volume product compound (12) 397.86 (1.00) (11.5) (0.029) Thenumbers in parenthesis in the above table are theoretical.

B. Second Variation

In the second variation, the reaction was conducted in a jacketed, 49 Lreactor equipped with a retreat curve agitator, nitrogen purge, andmetering pump. This reactor was charged with5-(4-piperidyl)-4-(4-pyrimidinyl)-3-(4-chlorophenyl)pyrazole (10)prepared as shown in Part E (1.9 Kg, 5.6 mol) and1-Methyl-2-pyrrolidinone (3.8 Kg, 38.3 mol). After initiating agitationat 75 rpm and allowing the mixture to stir for 6 minutes, the reactorwas further charged with butyl glycolate (11) (1.85 Kg, 14 mol, addedvia an addition funnel) and DBU (85.12 g, 0.54 mol) while continuing tostir the contents. The mixture was then heated to 110° C. over 23minutes, and then held at that temperature for 3 hours. A sample taken15 minutes after the 110° C. temperature had been reached indicated a87.2% conversion of the5-(4-piperidyl)-4-(4-pyrimidinyl)-3-(4-chlorophenyl)pyrazole (10), asample taken 60 minutes after the 110° C. temperature had been reachedindicated a 98.7% conversion of the5-(4-piperidyl)-4-(4-pyrimidinyl)-3-(4-chlorophenyl)pyrazole (10), and asample taken 120 minutes after the 110° C. temperature had been reachedindicated a 99.7% conversion of the5-(4-piperidyl)-4-(4-pyrimidinyl)-3-(4-chlorophenyl)pyrazole (10). Afterthe heating, the reaction mixture was cooled to approximately 25° C.over 1 hour and 5 minutes (the final baffle temperature was 28.5° C.,while the contents at the bottom were at 22.2° C.). A sample was taken,and then the reactor was charged with Ethanol 3A (12.35 Kg, 268 mol)over 55 minutes. After the ethanol was charged, a sample was taken. Themixture was then stirred for 65 minutes. A sample taken after the first30 minutes of the stirring indicated that 2.8% of theN-(2-hydroxyacetyl)-5-(4-piperidyl)-4-(4-pyrimidinyl)-3-(4-chlorophenyl)pyrazoleproduct (12) remained in solution, and a sample taken after 60 minutesof the stirring indicated that 3.4% of theN-(2-hydroxyacetyl)-5-(4-piperidyl)-4-(4-pyrimidinyl)-3-(4-chlorophenyl)pyrazoleproduct (12) was in solution. The mixture was next heated to reflux over1 hour and 2 minutes, and then maintained at reflux for 4 hours.Supernatant and solid samples were collected every 30 minutes. After the4 hours of refluxing, the mixture was cooled to 5° C. at a rate of 0.25°C./minute, and then maintained at that temperature overnight. Theresulting product was filtered, providing 17.46 Kg of filtrate. The cakewas washed with ethanol 3A (2×3.14 Kg (68.3 mol). The washed cake wasthen pull dried to LOD=0.67%. The amount of resulting wet cake was 2.00Kg (89.7% non-assay adjusted molar yield). The NMP concentration in thewet cake was determined using gas chromatography (“GC”) to be 518 ppm.The NMP concentration in the wet cake using the GC method with solidphase micro-extraction (“SPME”) was 580 ppm.

A portion of the wet cake (1.0 Kg, 2.51 mole) was then combined withethanol 3A (9.0 Kg, 11.38 L, 196 mol) by vacuum in the same reactor.Agitation was set to 80 RPM. The mixture was heated to reflux (i.e.,78-80° C.) over 33 minutes, and then held at reflux for 3 hours and 10minutes. Samples were taken after the first 1 hour and 10 minutes, afterthe first 2 hours and 10 minutes, and at the end of the 3 hours and 10minutes. The mixture was then cooled to 5° C. over 3 hours and 10minutes, and held at 5° C. overnight (i.e., approximately 16 hours and50 minutes). Samples were taken during the cool-down period. The solidswere filtered using a pressure filter, and a sample was taken from themother liquor. The amount of mother liquor collected was 8.68 Kg. Thecake was washed with ethanol 3A (2×3.14 Kg (68.3 mol), samples takenafter each wash). The cake was then pull dried for 1-2 hours toLOD=0.31%. This produced 0.892 Kg of wet cake (89.6% non-assay adjustedmolar yield). Total impurities in the cake were determined to be 0.46%(by weight), with NMP being present at a concentration of 0.01% (byweight) and 5-(4-piperidyl)-4-(4-pyrimidinyl)-3-(4-chlorophenyl)pyrazole(10) being at a concentration of 0.01% (by weight).

C. Third Variation

In the third variation, the reaction was conducted in a jacketed, 0.1 Lreactor equipped with an agitator, nitrogen purge, thermocouple, andcondenser. This reactor was charged with5-(4-piperidyl)-4-(4-pyrimidinyl)-3-(4-chlorophenyl)pyrazole (10)prepared as shown in Part E (1.9 Kg, 5.6 mol, LOC=0.40%) and1-Methyl-2-pyrrolidinone (3.8 Kg, 38.3 mol). After initiating stirringat 75 RPM, the reactor was further charged with butyl glycolate (11)(1.85 Kg, 14 mol) via an addition funnel and DBU (85.08 g, 0.56 mol)while continuing to stir the contents. The mixture was then heated to110° C. over 50 minutes, and then held at that temperature for 3 hoursand 25 minutes. A sample taken 15 minutes after the 110° C. temperaturehad been reached indicated a 89.8% conversion of the5-(4-piperidyl)-4-(4-pyrimidinyl)-3-(4-chlorophenyl)pyrazole (10), asample taken 60 minutes after the 110° C. temperature had been reachedindicated a 99.1% conversion of the5-(4-piperidyl)-4-(4-pyrimidinyl)-3-(4-chlorophenyl)pyrazole (10), and asample taken 180 minutes after the 110° C. temperature had been reachedindicated a 99.6% conversion of the5-(4-piperidyl)-4-(4-pyrimidinyl)-3-(4-chlorophenyl)pyrazole (10). Themixture was cooled to 40° C. over 2 hours and 20 minutes, and a samplewas taken. The reactor was then charged with ethanol 3A (0.76 Kg, 16.5mol) over 23 minutes. After the ethanol was added, a sample of the solidwas taken. The mixture was heated to reflux over 1 hour and 20 minutes,and then held at reflux for 4 hours. Supernatant and solid samples werecollected every 60 minutes. After the refluxing, the mixture was cooledto 5° C. at a rate of 0.25° C./min, and then held at that temperatureovernight. Samples of the solid and supernatant were collected. Themixture was then filtered, producing 3.54 Kg of filtrate (a sample ofthe filtrate was collected). The cake was washed with methyl t-butylether (“MTBE”, 2×3.14 Kg (35.6 mol), samples of the MTBE were collectedafter each wash). The washed cake was then pull dried for 1 hour and 15minutes (LOD=0.47%). This produced 2.56 Kg of wet cake. The non-assayadjusted yield was 92.1%. The NMP concentration in the wet cake wasdetermined using gas chromatography to be 518 ppm. The NMP concentrationin the wet cake using the GC method with SPME was 580 ppm. The wet cakewas then treated using two alternative procedures:

i. First Alternative Wet Cake Treatment

A portion of the wet cake prepared above (1.2 Kg, LOD-0.47%) was chargedto the same reactor, along with ethanol 3A (9.0 Kg, 11.38 L) via vacuum.This produced a thick slurry. The agitator speed was set to 95 RPM. Theslurry was heated to reflux (i.e., 78-80° C.) over 16 minutes, and thenheld at reflux for 5 hours. Samples were collected when the mixturefirst reached reflux, 102 minutes later, 162 minutes later, 186 minuteslater, and 251 minutes later. The mixture was then cooled to 5° C. over2 hours and 46 minutes, and then held at that temperature overnight(i.e., 11 hours and 59 minutes). The product was filtered with apressure filter producing 8.50 Kg of mother liquor (a sample of themother liquor was collected). The cake was washed with ethanol (2×1.60Kg, samples taken after each wash). The cake was then pull dried for afew hours. This produced 1.07 Kg of wet cake (LOD=18.0%). Aftercollecting a sample, the wet cake was then dried in a vacuum dryer at50° C. over a approximately a weekend. This produced 0.894 Kg wet cake(LOD=0.51%) with a 93.0% non-assay adjusted molar yield. Totalimpurities in the cake were determined to be 0.45% (by weight), with NMPbeing present at a concentration of 0.01% (by weight) and5-(4-piperidyl)-4-(4-pyrimidinyl)-3-(4-chlorophenyl)pyrazole (10) beingat a concentration of 0.01% (by weight).

ii. Second Alternative Wet Cake Treatment

A second portion of the wet cake (4 g) was charged to a nitrogen-purged,100 ml, jacketed vessel equipped with a chiller and an overhead stirrer.Ethanol 3A (34.2 g ethanol and 1.8 g methanol) and DBU (0.15 g) werepre-mixed, and then charged to the reactor while stirring the contentsat 250 RPM. Stirring was continued for 1 hour at room temperature. Thecontents were then heated to reflux for 1 hour, and then cooled to 0° C.for 3 hours. The next day, the solids were filtered and washed withethanol 3A. The resulting cake was pull-dried overnight with a housevacuum. The solids were then placed in a vacuum oven at approximately50° C. for another several hours.

Example 2 Preparation of an HCl salt ofN-(2-hydroxyacetyl)-5-(4-piperidyl)-4-(4-pyrimidinyl)-3-(4-chlorophenyl)pyrazole

A 10-mL, one-necked, round-bottomed flask equipped with a tubing adapterconnected to a nitrogen bubbler and a magnetic stirring bar was chargedwithN-(2-hydroxyacetyl)-5-(4-piperidyl)-4-(4-pyrimidinyl)-3-(4-chlorophenyl)pyrazole(0.398 g, 1.0 mmol) and 3.0 mL of ethanol. Hydrogen chloride was thenadded as a 1.0 M solution in ethanol (1.25 mL, 1.25 mmol). The resultingsuspension was stirred at room temperature for 1 hour, and then heatedto reflux. The hot solution was filtered to remove a small amount ofinsoluble material. The filtrate was then stirred at room temperaturefor 2 hours. The suspension that formed was then cooled in an ice-waterbath and stirred for an additional 2 hours. The suspension of crystalswas filtered, and the collected solid was dried for 2 hours at 40° C.under oil-pump vacuum to afford 0.381 g of the HCl salt as a yellowcrystalline solid. The salt had the following characteristics: ¹H NMR(DMSO-d₆; 400 MHz) δ: 1.7 (m, 2H), 1.9 (d, 2H), 2.7 (t, 1H), 3.0 (t,1H), 3.4 (m, 1H), 3.8 (d, 1H), 4.1 (q, 2H), 4.5 (d, 1H), 7.2 (d, 1H),7.4-7.5 (m, 4H), 8.7 (d, 1H), 9.3 (s, 1H). Microanalysis: Calculated for(C₂₀H₂₀ClN₅O₂).HCl.0.2(EtOH): C, 55.24; H, 5.04; N, 15.79. Found: C,54.97; H, 5.04; N, 15.72.

The above detailed description of preferred embodiments is intended onlyto acquaint others skilled in the art with the invention, itsprinciples, and its practical application so that others skilled in theart may adapt and apply the invention in its numerous forms, as they maybe best suited to the requirements of a particular use. This invention,therefore, is not limited to the above embodiments, and may be variouslymodified.

1. A process for making a substituted pyrazole, a tautomer of thesubstituted pyrazole, or a salt of the substituted pyrazole or tautomer,wherein: the substituted pyrazole corresponds in structure to Formula(I):

 and the process comprises: forming a mixture by a process comprisingintroducing a hydrazone and an optionally-substituted benzoyl halideinto a reactor, and heating the mixture to a temperature of greater than50° C.; and the hydrazone corresponds in structure to Formula (II):

 and the optionally-substituted benzoyl halide corresponds in structureto Formula (III):

 and R^(B) is halogen; and R^(3A), R^(3B), and R^(3C) are independentlyselected from the group consisting of hydrogen, halogen, hydroxy, cyano,amino, alkyl, aminoalkyl, monoalkylamino, dialkylamino, alkoxy, andalkoxyalkyl, wherein: any carbon of the alkyl, aminoalkyl,monoalkylamino, dialkylamino, alkoxy, or alkoxyalkyl optionally issubstituted with one or more substituents independently selected fromthe group consisting of halogen, hydroxy, and cyano; and one of Y¹, Y²,Y³, Y⁴, and Y⁵ is ═C(R⁴)—; and one of Y¹, Y², Y³, Y⁴, and Y⁵ is ═N—; andthree of Y¹, Y², Y³, Y⁴, and Y⁵ are independently selected from thegroup consisting of ═C(H)— and ═N—; and R⁴ is selected from the groupconsisting of hydrogen, halogen, cyano, hydroxy, thiol, carboxy, nitro,alkyl, carboxyalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl,alkylcarbonyl, carbocyclyl, carbocyclylalkyl, carbocyclylalkenyl,carbocyclyloxy, carbocyclylalkoxy, carbocyclyloxyalkyl, carbocyclylthio,carbocyclylsulfinyl, carbocyclylsulfonyl, heterocyclylthio,heterocyclylsulfinyl, heterocyclylsulfonyl, carbocyclylalkoxy,carbocyclylheterocyclyl, heterocyclylalkyl, heterocyclyloxy,heterocyclylalkoxy, amino, aminoalkyl, alkylamino, alkenylamino,alkynylamino, carbocyclylamino, heterocyclylamino, aminocarbonyl,alkoxy, alkoxyalkyl, alkenyloxyalkyl, alkoxyalkylamino,alkylaminoalkoxy, alkoxycarbonyl, carbocyclyloxycarbonyl,heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxycarbocyclylamino,alkoxycarbocyclylalkylamino, aminosulfinyl, aminosulfonyl,alkylsulfonylamino, alkoxyalkoxy, aminoalkoxy, aminoalkylaxnino,alkylaminoalkylamino, carbocyclylalkylamino,alkylaminoalkylaminoalkylamino, alkylheterocyclylamino,heterocyclylalkylamino, alkylheterocyclylalkylamino,carbocyclylalkylheterocyclylamino, heterocyclylheterocyclylalkylamino,alkoxycarbonylheterocyclylamino, alkylaminocarbonyl, alkylcarbonylamino,hydrazinyl, alkyihydrazinyl, and carbocyclylhydrazinyl, wherein: anysubstitutable member of such group optionally is substituted with one ormore substituents independently selected from the group consisting ofalkyl, alkenyl, hydroxy, halogen, haloalkyl, alkoxy, haloalkoxy, keto,amino, nitro, cyano, alkylsulfonyl, alkylsulfinyl, alkylthio,alkoxyalkyl, carbocyclyloxy, heterocyclyl, and heterocyclylalkoxy.
 2. Aprocess according to claim 1, wherein: Y² is ═C(R⁴)—, and Y⁴ Y⁵ are each═C(H)—.
 3. A process according to claim 2, wherein R⁴ is hydrogen.
 4. Aprocess according to claim 3, wherein R^(3C) is hydrogen.
 5. A processaccording to claim 4, wherein R^(3B) is hydrogen.
 6. A process accordingto claim 5, wherein: the substituted pyrazole corresponds in structureto the following formula:

 and the hydrazone corresponds in structure to the following formula:

 and the optionally-substituted benzoyl halide corresponds in structureto the following formula:


7. A process according to claim 6, wherein R^(B) is chloro.
 8. A processaccording to claim 7, wherein the mixture is heated at a temperature ofgreater than 50° C. for greater than 30 minutes.
 9. A process accordingto claim 8, wherein the mixture is heated at a temperature of greaterthan 50° C. for at least about 1 hour.
 10. A process according to claim7, wherein the mixture is heated to a temperature that is greater than50° C. and no greater than about 65° C.
 11. A process according to claim10, wherein the mixture is heated at a temperature of greater than 50°C. and no greater than about 65° C. for greater than 30 minutes.
 12. Aprocess according to claim 11, wherein the mixture is heated at atemperature of greater than 50° C. and no greater than about 65° C. forat least about 1 hour.